Methods and Compositions for Reducing Immunosupression by Tumor Cells

ABSTRACT

The present disclosure provides, in part, methods of discovering immunotherapy targets in vivo, therapeutic compositions (e.g., shRNA, immunoresponsive cells expressing shRNA and/or a chimeric antigen receptors (CAR)), and methods of use thereof.

RELATED APPLICATIONS

This application is a continuation of application Ser. No. 15/944,330,filed Apr. 3, 2018, which is a division of application Ser. No.14/897,210, filed Dec. 9, 2015, now U.S. Pat. No. 9,944,931, whichclaims the benefit under 35 U.S.C. § 371 of International ApplicationNo. PCT/US2014/041739, filed Jun. 10, 2014, which claims priority to andthe benefit of provisional applications U.S. Ser. No. 61/929,821, filedJan. 21, 2014, U.S. Ser. No. 61/921,303, filed Dec. 27, 2013 and U.S.Ser. No. 61/833,298, filed Jun. 10, 2013, the contents of all of whichare incorporated herein by reference in their entireties.

GOVERNMENT SUPPORT

This invention was made with government support under grant numbers R01CA173750, A1073861, and P30 CA014051 awarded by The National Institutesof Health. The government has certain rights in the invention.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has beensubmitted electronically in ASCII format and is hereby incorporated byreference in its entirety. The ASCII copy, created on Dec. 9, 2015, isnamed 14293-469sequence listing_ST25.txt and is 351 KB in size.

TECHNICAL FIELD

This invention relates to methods of discovering immunotherapy targetsin vivo, therapeutic compositions that modulate immunotherapy targets(e.g., shRNA, immunoresponsive cells expressing shRNA and, in some casesa receptor targeting a cancer cell, e.g., a chimeric antigen receptors(CAR)), and related methods of use.

BACKGROUND

Cytotoxic T cells play a central role in immune-mediated control ofcancers¹⁻³, and monoclonal antibodies that target inhibitory receptorson T cells can induce significant clinical benefit in patients withadvanced disease⁴⁻⁶. For survival, tumors have developed numerousimmunosuppressive mechanisms to promote their own growth and tosuccessfully evade the host immune system, effectively blocking theactivity of T cells in the tumor microenvironment. This is a centralissue in oncology because strong infiltration by CD8 T cells, which havecytotoxic function against tumor cells, is associated with a favorableprognosis in multiple types of human cancer^(1,3,8). This naturaldefense mechanism is severely blunted in the majority of patients bymultiple inhibitory signals emanating from the tumor, its stroma,regulatory T cells and myeloid cell populations.⁹⁻¹¹ Various molecularand cellular immunosuppressive mechanisms responsible for tumor evasionhave been identified. Certain of these mechanisms target immuneantitumor effector cells. However, many of the regulatory mechanismsthat result in loss of T cell function within immunosuppressive tumorsremain unknown. Improving on the limited success of cancer immunotherapyrequires new approaches to inhibit immunosuppressive pathways initiatedby tumor cells to evade the host immune system.

SUMMARY

The present disclosure provides targets for inhibiting immunosuppressivepathways used by tumor cells to inactivate and/or suppress immune cells.

The disclosure also provides compositions and methods related to shRNAwith therapeutic potential.

The disclosure also provides immunoresponsive cells, including T cells(e.g., cells targeting a tumor antigen) expressing at least one shRNA orother nucleic acid molecule capable of silencing genes that inhibit Tcell function.

The disclosure also provides immunoresponsive cells, including T cells,harboring at least one vector expressing a shRNA and at least onechimeric antigen receptor directed to a tumor antigen.

In some embodiments, the disclosure provides immunoresponsive cellshaving tumor specificity comprising a vector encoding a shRNA capable ofsilencing genes that inhibit T cell function. In some aspects, the shRNAsequence reduces the expression of a gene selected from the groupconsisting of Ppp2r2d, Eif2ak3, Arhgap5, Smad2, Akap81, Rbks, Egr2,Dgka, Cblb, Mdfic, Entpd1, Dgkz, Vamp7, Hipk1, Nuak2, Alk, Pdzk1ip1,Inpp5b, Socs1, Jun, Nptxr, Socs3, F11r, Fyn, Ype2, Pkd1, Grk6, Cdkn2a,Sbf1, Ipmk, Rock1, Stk17b, Mast2, Pdp1, Yes1, Met, Ppm1g, Blvrb, Tnk1,Prkab2, Trpm7 or Ppp3cc. In another aspect, the shRNA comprises 15contiguous nucleotides complementary to a nucleic acid sequence selectedfrom the group consisting of SEQ ID NOs: 604-620 and 653-678. In someaspects, the immunoresponsive cell further comprises a vector encoding atumor-specific T-cell receptor. In some aspects, the immunoresponsivecell is selected from the group consisting of a tumor-infiltratinglymphocyte (TIL), a Natural Killer T cell (NKT), a cytotoxic Tlymphocyte (CTL), and a CD4 T cell.

In some embodiments, the immunoresponsive cell comprises a vectorencoding a CAR, wherein the CAR comprises an antigen binding domain, atransmembrane domain, and a stimulatory domain. In some aspects, theantigen binding domain binds a tumor antigen or pathogen antigen.Exemplary tumor antigens include, for example, prostate-specificmembrane antigen (PSMA), Carcinoembryonic Antigen (CEA), CD19, CD20,CD22, ROR1, mesothelin, CD333/IL3Ra, c-Met, Glycolipid F77, EGFRvIII,GD-2, NY-ESO-1 TCR, ERBB2, BIRC5, CEACAM5, WDR46, BAGE, CSAG2, DCT,MAGED4, GAGE1, GAGE2, GAGE3, GAGE4, GAGE5, GAGE6, GAGE7, GAGE8, IL13RA2,MAGEA1, MAGEA2, MAGEA3, MAGEA4, MAGEA6, MAGEA9, MAGEA10, MAGEA12,MAGEB1, MAGEB2, MAGEC2, TP53, TYR, TYRP1, SAGE1, SYCP1, SSX2, SSX4,KRAS, PRAME, NRAS, ACTN4, CTNNB1, CASP8, CDC27, CDK4, EEF2, FN1, HSPA1B,LPGAT1, ME1, HHAT, TRAPPC1, MUM3, MYO1B, PAPOLG, OS9, PTPRK, TPI1, ADFP,AFP, AIM2, ANXA2, ART4, CLCA2, CPSF1, PPIB, EPHA2, EPHA3, FGF5, CA9,TERT, MGAT5, CEL, F42, CAN, ETV6, BIRC7, CSF1, OGT, MUC1, MUC2, MUM1,CTAG1A, CTAG2, CTAG, MRPL28, FOLH1, RAGE, SFMBT1, KAAG1, SART1, TSPYL1,SART3, SOX10, TRG, WT1, TACSTD1, SILV, SCGB2A2, MC1R, MLANA, GPR143,OCA2, KLK3, SUPT7L, ARTC1, BRAF, CASP5, CDKN2A, UBXD5, EFTUD2, GPNMB,NFYC, PRDX5, ZUBR1, SIRT2, SNRPD1, HERV-K-MEL, CXorf61, CCDC110,VENTXP1, SPA17, KLK4, ANKRD30A, RAB38, CCND1, CYPIB1, MDM2, MMP2,ZNF395, RNF43, SCRN1, STEAP1, 707-AP, TGFBR2, PXDNL, AKAP13, PRTN3,PSCA, RHAMM, ACPP, ACRBP, LCK, RCVRN, RPS2, RPL10A, SLC45A3, BCL2L1,DKK1, ENAH, CSPG4, RGS5, BCR, BCR-ABL, ABL-BCR, DEK, DEK-CAN, ETV6-AML1,LDLR-FUT, NPM1-ALK1, PML-RARA, SYT-SSX1, SYT-SSX2, FLT3, ABL1, AML1,LDLR, FUT1, NPM1, ALK, PML1, RARA, SYT, SSX1, MSLN, UBE2V1, HNRPL,WHSC2, EIF4EBP1, WNK2, OAS3, BCL-2, MCL1, CTSH, ABCC3, BST2, MFGE8,TPBG, FMOD, XAGE1, RPSA, COTL1, CALR3, PA2G4, EZH2, FMNL1, HPSE, APC,UBE2A, BCAP31, TOP2A, TOP2B, ITGB8, RPA1, ABI2, CCNI, CDC2, SEPT2,STAT1, LRP1, ADAM17, JUP, DDR1, ITPR2, HMOX1, TPM4, BAAT, DNAJC8, TAPBP,LGALS3BP, PAGE4, PAK2, CDKN1A, PTHLH, SOX2, SOX11, TRPM8, TYMS, ATIC,PGK1, SOX4, TOR3A, TRGC2, BTBD2, SLBP, EGFR, IER3, TTK, LY6K, IGF2BP3,GPC3, SLC35A4, HSMD, H3F3A, ALDH1A1, MFI2, MMP14, SDCBP, PARP12, MET,CCNB1, PAX3-FKHR, PAX3, FOXO1, XBP1, SYND1, ETV5, HSPA1A, HMHA1, TRIM68,and any combination thereof. In some aspects, the antigen binding domainis an antigen-binding fragment of an antibody (e.g., Fab or a scFv). Theintracellular domains of such CARs contain cytoplasmic signaling domainsderived from the T cell receptor and costimulatory molecules.

In some embodiments, the vector is a plasmid, retroviral vector, orlentiviral vector.

In some embodiments, the disclosure provides isolated nucleic acidmolecules encoding a shRNA sequence. In another embodiment, thedisclosure provides isolated nucleic acid molecules encoding a CAR. Inyet another embodiment, the disclosure provides isolated nucleic acidmolecules encoding a CAR and a shRNA sequence. In some aspects, theisolated nucleic acid encodes a shRNA sequence reduces the expression ofa gene selected from the group consisting of Ppp2r2d, Eif2ak3, Arhgap5,Smad2, Akap81, Rbks, Egr2, Dgka, Cblb, Mdfic, Entpd1, Dgkz, Vamp7,Hipk1, Nuak2, Alk, Pdzk1ip1, or Inpp5b, Socs1, Jun, Nptxr, Socs3, F11r,Fyn, Ypel2, Pkd1, Grk6, Cdkn2a, Sbf1, Ipmk, Rock1, Stk17b, Mast2, Pdp1,Yes1, Met, Ppm1g, Blvrb, Tnk1, Prkab2, Trpm7 or Ppp3cc. In anotheraspect, the isolated nucleic acid encodes a shRNA comprising 15contiguous nucleotides complementary a nucleic acid sequence selectedfrom the group consisting of SEQ ID NOs: 604-620 and 653-678.

In some embodiments, the isolated nucleic acid encodes a CAR comprisingan antigen binding domain, a transmembrane domain, a stimulatory domain,and a co-stimulatory domain. In some embodiments, the antigen bindingdomain is an antigen-binding fragment of an antibody (e.g., Fab or ascFv). In some embodiments, the antigen binding domain is a cytoplasmicsignaling domain derived from the T cell receptor and costimulatorymolecules.

In some embodiments, the antigen-binding domain binds tumor antigen(e.g., a tumor antigen associated with a solid tumor, lymphoid tumor,melanoma, carcinoma, sarcomas, adenocarcinoma, lymphoma, leukemia,kidney, breast, lung, bladder, colon, ovarian, prostate, pancreas,stomach, brain, head and neck, skin, uterine, testicular, glioma,esophagus, and liver cancer).

In some embodiments the disclosure provides vectors comprising anisolated nucleic acid encoding a shRNA sequence, an isolated nucleicacid encoding a CAR, or an isolated nucleic acid encoding a CAR and ashRNA sequence. In some aspects, the vector is a plasmid, lentiviralvector, retroviral vector, adenoviral vector, adeno-associated viralvector. The shRNA can be operably linked to RNA polymerase II promoteror an RNA polymerase III promoter.

In yet other embodiments, the invention provides compositions comprisingimmunoresponsive cells according to the invention, and apharmaceutically acceptable carrier.

In some embodiments, the disclosure provides immunoresponsive cellstransfected with a first vector encoding a CAR and a second vectorencoding a shRNA sequence. In some aspects, the shRNA sequence reducesthe expression of a gene selected from the group consisting of Ppp2r2d,Eif2ak3, Arhgap5, Smad2, Akap81, Rbks, Egr2, Dgka, Cblb, Map3k3, Mdfic,Entpd1, Dgkz, Vamp7, Hipk1, Nuak2, Alk, Pdzk1ip1, Inpp5b, Socs1, Jun,Nptxr, Socs3, F11r, Fyn, Ypel2, Pkd1, Grk6, Cdkn2a, Sbf1, Ipmk, Rock1,Stk17b, Mast2, Pdp1, Yes1, Met, Ppm1g, Blvrb, Tnk1, Prkab2, Trpm7 orPpp3cc. In another aspect, the shRNA comprise 15 contiguous nucleotidescomplementary a nucleic acid sequence selected from the group consistingof SEQ ID NOs: 604-620 and 653-678. In some aspects, theimmunoresponsive cell further comprises a vector encoding atumor-specific T-cell receptor. In some aspects, the immunoresponsivecell is selected from the group consisting of a tumor-infiltratinglymphocyte (TIL), a Natural Killer T cell (NKT), a cytotoxic Tlymphocyte (CTL), and a CD4 T cell.

In some embodiments, the disclosure provides methods for treating cancerin a subject, the method comprising administering to the subject anautologous T cell modified to express a tumor-specific T-cell receptoror CAR and an shRNA, wherein the shRNA sequence reduces the expressionof a gene selected from the group consisting of Ppp2r2d, Eif2ak3,Arhgap5, Smad2, Akap81, Rbks, Egr2, Dgka, Cblb, Map3k3, Mdfic, Entpd1,Dgkz, Vamp7, Hipk1, Nuak2, Alk, Pdzk1ip1, Inpp5b, Socs1, Jun, Nptxr,Socs3, F11r, Fyn, Ypel2, Pkd1, Grk6, Cdkn2a, Sbf1, Ipmk, Rock1, Stk17b,Mast2, Pdp1, Yes1, Met, Ppm1g, Blvrb, Tnk1, Prkab2, Trpm7 or Ppp3cc. Insome aspects, the shRNA sequence comprises 15 contiguous nucleotidescomplementary to a nucleic acid sequence selected from the groupconsisting of: SEQ ID NOs: 604-620 and 653-678; and wherein the CARcomprises an antigen binding domain, a transmembrane domain, astimulatory domain, and a co-stimulatory domain. In some aspects, theCAR comprises an antigen binding domain, a transmembrane domain, astimulatory domain, and a co-stimulatory domain.

In some embodiments, the disclosure provides methods for treating cancerin a subject, the method comprising administering to the subject anautologous T cell modified to express a tumor-specific T-cell receptoror CAR and an shRNA of the invention. In yet another embodiment, thedisclosure provides methods for treating cancer in a subject in needthereof by silencing genes that inhibit T cell function comprisingadministering to the subject an immunoresponsive cell comprising avector, the vector encoding a tumor-specific T-cell receptor or a CARand a shRNA sequence of the invention.

In some embodiments, the disclosure provides methods for identifying agene that inhibits the function of an immunoresponsive T cell, themethod comprising providing a population of immunoresponsive T cellsharboring vectors expressing a shRNA, contacting the population ofimmunoresponsive T cells with an immunosuppressive tumor, determiningwhether a shRNA restores T cell function within the immunosuppressivetumor, and identifying a gene associated with a shRNA that restores Tcell function within the tumor as a gene that inhibits the function oftumor-infiltrating T cells.

In some embodiments, the disclosure provides methods for increasing theimmune response in a subject in need thereof, the method comprisingadministering a therapeutic agent that modulates the activity of a geneselected from the group consisting of Ppp2r2d, Eifak3, Arhgap5, Smad2,Akap81, Rbks, Egr2, Dgka, Cblb, Mdfic, Entpd1, Dgkz, Vamp7, Hipk1,Nuak2, Alk, Pdzk1ip1, Inpp5b, Socs1, Jun, Nptxr, Socs3, F11r, Fyn,Ypel2, Pkd1, Grk6, Cdkn2a, Sbf1, Ipmk, Rock1, Stk17b, Mast2, Pdp1, Yes1,Met, Ppm1g, Blvrb, Tnk1, Prkab2, Trpm7 and Ppp3cc.

In some cases the sequence encoding an shRNA comprises a first sequencecomprising 15-25 (15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25)nucleotides complementary to any of SEQ ID NOs: 604-620 or SEQ ID NOs:653-678 and a second sequence that is the reverse complement of thefirst sequence with one or no mismatches (i.e., is perfectlycomplementary to the first sequence), and a third sequence of 5-9nucleotides positioned between the first and second sequences.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Methods and materials aredescribed herein for use in the present invention; other, suitablemethods and materials known in the art can also be used. The materials,methods, and examples are illustrative only and not intended to belimiting. All publications, patent applications, patents, sequences,database entries, and other references mentioned herein are incorporatedby reference in their entirety. In case of conflict, the presentspecification, including definitions, will control.

Other features and advantages of the invention will be apparent from thefollowing detailed description and figures, and from the claims.

DESCRIPTION OF DRAWINGS

The patent or application file contains at least one drawing executed incolor. Copies of this patent or patent application publication withcolor drawing(s) will be provided by the Office upon request and paymentof the necessary fee.

FIG. 1 is a schematic diagram demonstrating an exemplary approach for invivo discovery of shRNAs that enhance T cell infiltration andaccumulation within the tumor microenvironment.

FIG. 2 is a set of graphs showing representative flow cytometry plots ofCD8⁺ T cells from Rag1−/−/OT-I TCR transgenic mice following infectionwith an shRNA vector. Transduction efficiency was determined based onexpression of the Thy1.1 reporter encoded by the lentiviral vector.Cytokine-cultured T cells expressing the LacZ control shRNA were thenstained with a panel of activation markers (black lines; isotypecontrol, shaded). The majority of infected T cells exhibited a centralmemory phenotype (CD62L⁺ CD44⁺).

FIG. 3 is a set of graphs showing representative flow cytometry plots ofOT-I T cells sorted from tumors and secondary lymphoid organs for deepsequencing analysis (dLN, tumor-draining lymph node; irLN, irrelevantlymph node). CD8⁺Vα2⁺Vβ5⁺Thy1.1⁺ cells were sorted and genomic DNA wasextracted for PCR amplification of the shRNA cassette.

FIG. 4 is a set of graphs showing deep sequencing data from in vivoshRNA pool screen. Upper row, sequence reads for all genes in a pool intumor, irrelevant (irLN) and draining lymph node (dLN); lower row, threeindividual genes (LacZ, negative control) are plotted in comparison tospleen for tumors, irrelevant lymph nodes (irLN) and tumor-draininglymph nodes (dLN). Sequence reads are plotted for these tissues versusspleen. Dashed lines indicate a deviation by log 2 from diagonal.

FIG. 5 is a set of graphs showing deep sequencing data from T celldysfunction screen. shRNA sequencing reads for genes positive insecondary screen are plotted in comparison to spleen for tumors (red),irrelevant lymph nodes (irLN, blue) and tumor-draining lymph nodes (dLN,green), with dashed lines indicating a deviation of log 2 from thediagonal. Data show enrichment of particular shRNAs representing thesegenes in tumors compared to spleens or lymph nodes.

FIG. 6 is a graph showing flow cytometry based quantification of OT-ICD8⁺ T cell enrichment in tumors relative to spleen. The percentage ofshRNA-expressing OT-I T cells was determined by flow cytometry intumors/spleens by gating on reporter proteins in CD8⁺Vα2³⁰ Vβ5⁺ T cells.Statistical significance was determined for each experimental shRNAagainst LacZ shRNA (fold enrichment tumor/spleen) (n=3; * p<0.05, *p<0.01, Student's t-test).

FIG. 7 is a set of graphs showing representative flow cytometry plots ofcell enrichment in tumor transduced with shRNA vectors (LacZ, Akap8I,Smad2, Rbks, Dgkz). The percentage of shRNA-expressing OT-I T cells wasdetermined by flow cytometry in tumors/spleens by gating on reporterproteins in CD8⁺Vα2⁺Vβ5⁺ T cells.

FIGS. 8a-8b are a set of graphs showing flow cytometry-basedquantification of CD4+ and CD8+ T cell enrichment in tumors.shRNA-expressing T cells were identified in tumors and spleens usingThy1.1 reporter (% Thy1.1+CD8 T cells or CD4+ T cells, top and bottompanels). Total numbers of LacZ or Ppp2r2d shRNA-expressing T cells weredetermined in tumors and spleens 7 days following transfer of 2×10⁶shRNA-expressing cells (right panels). Fold-enrichment of Ppp2r2d versusLacZ shRNA-expressing T cells in tumors is indicated.

FIG. 9 is a graph showing reversal of Ppp2r2d shRNA-mediated T cellexpansion in tumors by Ppp2r2d cDNA with a mutated shRNA binding sitebut preserved protein sequence. The three cell populations wereidentified based on co-expressed reporters; fold-enrichment wascalculated based on percentage of reporter-positive cells in tumorsversus spleens.

FIG. 10a describes the generation of mutant Ppp2r2d cDNA with preservedprotein sequence but disrupted shRNA binding site. EL4 cells weretransduced with mutant or wild type Ppp2r2d cDNA on a vector alsocontaining GFP. GFP-positive cells were sorted to purity and transducedwith LacZ or Ppp2r2d shRNA vectors expressing a Thy1.1 reporter.shRNA-transduced (Thy1.1⁺) cells were analyzed by flow cytometry for GFPexpression. The Ppp2r2d shRNA reduced GFP levels when wild-type Ppp2r2d,but not when mutant Ppp2r2d was expressed. (SEQ ID NOS. 679-681 shown.)

FIG. 10b demonstrates that expression of Ppp2r2d mutant cDNA preventsphenotype induced by Ppp2r2d shRNA. OT-I T cells were transduced with avector encoding LacZ shRNA, Ppp2r2d shRNA or Ppp2r2d shRNA plus mutantPpp2r2d cDNA. The different cell populations were normalized fortransduction efficiency and co-injected into B16-Ova tumor bearing mice.The percentage of each T cell population in tumors and spleens wasquantified by gating on CD8³⁰ Vα2⁺Vβ5⁺ T cells; transduced cells weredetected based on expression of Thy1.1 or Ametrine/GFP fluorescentreporters (representative data from 2 independent experiments, n=3 miceper experiment).

FIG. 10c is a graph demonstrating real-time PCR analysis for Ppp2r2dexpression in OT-I T cells transduced with LacZ shRNA, Ppp2r2d shRNA,and Ppp2r2d shRNA plus Ppp2r2d mutant cDNA. Data represent biologicalreplicates (n=3), each value represents mean+/−s.d.

FIG. 11 is a graph demonstrating real-time qPCR analysis for Ppp2r2dmRNA levels in OT-I T cells transduced with LacZ shRNA or one of threePpp2r2d shRNAs identified in the screen.

FIG. 12a is a table demonstrating enrichment of particular shRNAs intumor versus spleen which was calculated based on deep sequencingresults from the secondary screen.

FIG. 12b demonstrates clustering of mean expression levels for mRNAsfound to be significantly regulated by T cells in or tumors expressingthe LacZ control shRNA or one of five experimental shRNAs. Significantexpression differences were defined as an Anova p value<0.01 between Tcells expressing LacZ control shRNA or one of five experimental shRNAs(Alk, Arhgap5, Egr2, Ptpn2 or Ppp2r2d) (JMP-Genomics 6.0, SAS InstituteInc.). mRNAs significantly regulated in one or more treatment groups areshown after clustering (Fast Ward).

FIG. 12c is a Venn diagram showing overlaps between expressionsignatures by tumor-infiltrating T cells transduced with one of the fiveexperimental shRNAs (signatures defined as an Anova p<0.01 as describedabove). Indicated are the numbers of overlapping probe IDs for anycombination of the 5 signatures, as indicated by the overlapping ovals.The significance of the overlaps versus that expected by random chance(Fishers Exact Test) is shown in the accompanying table.

FIG. 13a is a set of graphs showing representative flow cytometry plotsof demonstrating the frequency of Ppp2r2d or LacZ shRNA-transduced CD8 Tcells in tumors on day 1.

FIG. 13b are a pair of graphs demonstrating the degree of proliferation(based on CFSE dilution) by Ppp2r2d shRNA-transduced CD8 T cellscompared to LacZ shRNA-transduced T cells in tumors on days 1, 3, 5, and7.

FIG. 13c is a set of graphs demonstrating that Ppp2r2d-silencinginhibits T cell apoptosis upon encounter of tumor cells. CFSE-labeledOT-I T cells were co-cultured with B16-Ova tumor cells for 72 hours.Cells were stained with CD8 and annexin V.

FIG. 13d is a set of graphs demonstrating intracellular staining foranti-apoptotic proteins. OT-I T cells expressing LacZ or Ppp2r2d shRNAwere co-cultured with B16-Ova tumor cells for 48 hours and then stainedwith isotype control (grey) and phospho-AKT (Ser473), phospho-Bad (Ser112) or Bcl-2 antibodies.

FIG. 13e is a graph demonstrating increased IFN-γ secretion byPpp2r2d-silenced T cells. OT-I T cells isolated from B16-Ovatumor-bearing mice were assayed for IFN-γ expression by intracellularstaining.

FIG. 13f is a set of graphs demonstrating Ppp2r2d-silenced T cellsexpand in tumors even without presentation of tumor antigens byprofessional antigen presenting cells. LacZ or Ppp2r2d shRNA-expressingOT-I T cells were transferred into day 14 B16-Ova tumor-bearing C57BL/6or h2m−/− mice. shRNA-expressing T cells were identified based onexpression of teal fluorescent protein (TFP) or Thy1.1 (fold enrichmentin tumors compared to spleens).

FIG. 13g is a graph demonstrating that Ppp2r2d-silencing inhibits T cellapoptosis upon encounter of tumor cells. CFSE-labeled OT-I T cells wereco-cultured with B16-Ova tumor cells for 72 hours (activated caspase-3).

FIG. 14 is a set of graphs demonstrating OT-I T cells expressing LacZ orPpp2r2d shRNAs labeled with CFSE and stimulated with CD3 antibody for 72h. Cells were then stained with CD8 and annexin V and analyzed by flowcytometry.

FIG. 15 is a set of graphs demonstrating accumulation of Ppp2r2dshRNA-expressing T cells in tumors and tumor-draining lymph nodes, butnot other secondary lymphoid organs. OT-I T cells expressing Ppp2r2d orLacZ shRNAs were labeled with CFSE and injected into B16-Ovatumor-bearing mice. T cells were isolated from the indicated organs ondays 1, 3, 5 and 7 to examine the extent of T cell accumulation based ondilution of the CSFE dye.

FIGS. 16a-c are a set of graphs demonstrating that the silencing ofPpp2r2d enhances anti-tumor activity of CD4 and CD8 T cells. T cellswere activated with anti-CD3/CD28 beads, infected with lentivirusesdriving LacZ or Ppp2r2d shRNA expression and injected into B16-Ova (a,b)or B16 (c) tumor-bearing mice. Tumor size was measured every three daysfollowing T cell transfer using calipers on the two longest axes. a,bCD4⁺ TRP-1 and/or CD8⁺ OT-I T cells (2×10⁶) were transferred (day 12 and17) into mice bearing day 12 B16-Ova tumors. Tumor burden (a) andsurvival (b) were assessed. c, CD4⁺ TRP-1 and CD8⁺ pmel-1 T cells (3×10⁶CD4⁺ TRP-1 plus 3×10⁶ CD8⁺ pmel-1) were transferred (day 10 and 15) intomice with day 10 B16 tumors. Log-rank (Mantel-Cox) test was performedusing GraphPad Prism version 6 comparing survival of mice treated withLacZ versus Ppp2r2d shRNA-expressing T cells.

FIG. 17 is a set of graphs demonstrating FACS analysis of T cellenrichment in tumors compared to spleen for cells expressing a panel ofPpp2r2d or Cblb shRNAs (upper panels). Ppp2r2d and Cblb mRNA levels weremeasured by qPCR prior to T cell transfer (lower panels). Data representbiological replicates (n=3), each value represents mean+/−s.d.

FIG. 18 is a set of graphs demonstrating Ppp2r2d protein quantificationby mass spectrometry with labeled synthetic peptides (AQUA, ratio ofendogenous to AQUA peptides). Representative data from two independentexperiments (a-d); Two-sided student's t-test, * P<0.05, ** P<0.01;mean+/−s.d.

FIG. 19 is a graph demonstrating qPCR analysis for Ppp2r2d mRNA intumor-infiltrating OT-I T cells (day 7).

FIG. 20a are graphs showing representative flow cytometry plotsdemonstrating proliferation of Ppp2r2d shRNA-expressing T cells intumors and tumor-draining lymph nodes. OTI T cells expressing Ppp2r2d orLacZ shRNAs were labeled with CFSE and injected into B16-Ovatumor-bearing mice. T cells were isolated from the indicated organs ondays 1, 3, 5 and 7 to examine the extent of T cell proliferation basedon CFSE dilution. T cells that had not diluted CFSE (nondividing cells)were quantified (right).

FIG. 20b are graphs showing representative flow cytometry plotsdemonstrating viability of tumor-infiltrating T cells. OT-I T cellsexpressing Pp2r2d or LacZ shRNAs were injected into B16-Ovatumor-bearing mice. T cells were isolated on day 7 and apoptosis wasassessed by intracellular staining with an antibody specific foractivated caspase-3 (some T cell death may have been caused by theisolation procedure from tumors).

FIG. 20c are graphs showing representative flow cytometry plotsdemonstrating intracellularcytokine staining for IFNγ by LacZ andPpp2r2d shRNA-expressing T cells harvested from B16-Ova tumors; T cellswere labeled with CFSE prior to injection. Data for all experiments arerepresentative of two independent trials. Statistical analysis wasperformed on biological replicates (n=3); * P<0.05, ** P<0.01, two-sidedStudent's t-test. Each value represents mean+/−s.d.

FIGS. 21a-c are a series of graphs demonstrating ex vivo analysis ofcytokine production by tumor-infiltrating OT-I T cells at a single-celllevel using a nanowell device (84,672 wells of picoliter volume). a,Representative single cells in nanowells and corresponding patterns ofcytokine secretion. b, Percentage of T cells secreting indicatedcytokines. c, Cytokine secretion rates calculated from standard curves(mean+/−s.d., Mann Whitney test * P<0.05).

FIG. 22a is a set of graphs showing representative flow cytometry plotsdemonstrating that the majority of adoptively transferred OT-I cellshave a memory phenotype in lymph nodes but an effector phenotype intumors. Cytokine pre-treated cells expressing Ppp2r2d or LacZ shRNAswere injected into mice bearing day 14 B16-Ova tumors. On day 7following transfer, T cells were harvested from the indicated organs andstained with CD62L and CD44 antibodies. FACS analysis ofshRNA-expressing OT-I cells was performed by gating on CD8/Thy1.1double-positive cells.

FIG. 22b is a set of graphs showing representative flow cytometry plotsdemonstrating analysis of exhaustion markers. OT-I cells were harvestedfrom draining lymph nodes and tumors of mice and stained with antibodiesspecific for TIM-3, LAG-3, PD-1 and CD25. For all experiments (n=3biological replicates; * P<0.05, ** P<0.01, Two-sided Student's t-test);each value represents mean+/−s.d.

FIG. 23a is a set of graphs showing demonstrating intracellular stainingfor granzyme B by OT-I T cells in tumor-draining lymph nodes and tumors.

FIG. 23b is a pair of images and a graph demonstrating infiltration ofshRNA-expressing T cells into tumors. OT-I T cells were transduced withLacZ or Ppp2r2d shRNA vectors encoding a GFP reporter and injected intoB6-Ova tumor-bearing mice. After 7 days, tumors were excised and frozensections stained with anti-GFP and DAPI to enumerate shRNAexpressingOT-I T cells in tumors.

FIG. 23c is a pair of images and a graph demonstrating TUNELimmunohistochemistry performed on tissue sections and apoptotic cellswere quantified.

FIG. 23d is a set of graphs demonstrating MHC class I expression bytumor cells. Tumors were digested with collagenase and stained withCD45.2 and H-2Kb antibodies. FACS analysis for H-2Kb expression wasperformed by gating on CD45.2-negative melanoma cells. Data representbiological replicates (n=3), each value represents mean+/−s.d.

DETAILED DESCRIPTION

The present disclosure is based, in part, on the observation that theregulatory mechanisms that result in loss of T cell function withinimmunosuppressive tumors can be systematically discovered in vivo usinga pooled small hairpin RNA (shRNA) screening approach aimed atidentifying genes that block the function of tumor infiltrating T-cells.As described in the background section above, tumor associatedimmunosuppressive mechanisms actively block the activity of T cells inthe tumor microenvironment. The methods described herein identify shRNAsthat enable robust T cell infiltration and accumulation in tumors,despite the multiple inhibitory signals. As described below, the methodsidentify shRNA that silence expression of genes responsible forimmunosuppression by tumors, allowing for enhanced T cell infiltrationand accumulation in tumors and resistance to apoptosis.

In some instances, the disclosure provides methods for specificallyidentifying regulatory mechanisms that result in the loss of T cellfunction within the tumor microenvironment. These methods can include:providing a population of T cells harboring vectors expressing a shRNA;contacting the population of T cells with an immunosuppressive tumor;determining whether a shRNA restores T cell function (e.g., restoresability of T cell to infiltrate and proliferate within the tumormicroenvironment) within the immunosuppressive tumor; identifying a geneassociated with a shRNA that restores T cell function within the tumoras a gene that inhibits T cell function within the tumormicroenvironment.

The disclosure provides target genes for reducing the immunosuppressiveeffect of tumors. The expression of the target genes can be reduced inimmune cells, e.g., T cells that recognize tumor associated antigens,and the reduction in expression of the target genes can increase theability of the cells to evade tumor associated immunosuppressivemechanisms.

The disclosure provides shRNAs that reduce (e.g., silence, eliminate,knock down, knock out, or decrease) expression of genes that impair thefunction of tumor infiltrating T-cells. These shRNA were identified fromthe transfer of shRNA transduced T cells into tumors, followed by deepsequencing to quantify the representation of all shRNAs in the tumor andlymphoid organs. Representative shRNA disclosed herein include shRNAthat reduce the activity of genes including, for example, Ppp2r2d,Eif2ak3, Arhgap5, Smad2, Akap81, Rbks, Egr2, Dgka, Cblb, Mdfic, Entpd1,Dgkz, Vamp7, Hipk1, Nuak2, Alk, Pdzk1ip1, Inpp5b, Socs1, Jun, Nptxr,Socs3, F11r, Fyn, Ypel2, Pkd1, Grk6, Cdkn2a, Sbf1, Ipmk, Rock1, Stk17b,Mast2, Pdp1, Yes1, Met, Ppm1g, Blvrb, Tnk1, Prkab2, Trpm7 and Ppp3cc.

In some instances, the disclosure provides therapeutic compositions(e.g., including isolated nucleic acid molecules, vectors expressingnucleic acid molecules encoding the shRNA) related to the shRNAs thatsilence expression of genes that block the function of tumorinfiltrating T-cells. In other aspects, the disclosure provides modifiedimmunoresponsive cells (e.g., T cells, including Natural Killer T cells(NKT), a cytotoxic T lymphocytes (CTL), and a regulatory T cells) thatharbor vectors capable of expressing the shRNA described herein. Inanother aspect, the modified immunoresponsive cells further harbor avector capable of expressing a CAR having an antigen binding domain thattargets a tumor specific antigen.

RNA Interference One of the most important recent discoveries inbiomedical research is the RNA interference (RNAi) pathway, which isused by cells to regulate the activity of many genes. The principles ofRNAi have opened many new possibilities for the identification oftherapeutic targets. RNA interference (RNAi) is an effective tool forgenome-scale, high throughput analysis of gene function. The term “RNAinterference” (RNAi), also called post transcriptional gene silencing(PTGS), refers to the biological process in which RNA molecules inhibitgene expression. An “RNA interfering agent” as used herein, is definedas any agent that interferes with or inhibits expression of a targetgene, e.g., a target gene of the invention, by RNA interference (RNAi).Such RNA interfering agents include, but are not limited to, nucleicacid molecules including RNA molecules which are homologous to thetarget gene, e.g., a target gene of the invention, or a fragmentthereof, short interfering RNA (siRNA), short hairpin RNA (shRNA), andsmall molecules which interfere with or inhibit expression of a targetgene by RNA interference (RNAi).

“RNA interference (RNAi)” is a process whereby the expression orintroduction of RNA of a sequence that is identical or highly similar toa target gene results in the sequence specific degradation or PTGS ofmessenger RNA (mRNA) transcribed from that targeted gene, therebyinhibiting expression of the target gene. This process has beendescribed in plants, invertebrates, and mammalian cells. RNAi can alsobe initiated by introducing nucleic acid molecules, e.g., syntheticsiRNAs or RNA interfering agents, to inhibit or silence the expressionof target genes. As used herein, “inhibition of target gene expression”or “inhibition of marker gene expression” includes any decrease inexpression or protein activity or level of the target gene (e.g., amarker gene of the invention) or protein encoded by the target gene,e.g., a marker protein of the invention. The decrease may be of at least30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 99% or more as compared to theexpression of a target gene or the activity or level of the proteinencoded by a target gene which has not been targeted by an RNAinterfering agent.

“Short interfering RNA” (siRNA), also referred to herein as “smallinterfering RNA” is defined as an agent which functions to inhibitexpression of a target gene. These are the effector molecules forinducing RNAi, leading to posttranscriptional gene silencing withRNA-induced silencing complex (RISC). In addition to siRNA, which can bechemically synthesized, various other systems in the form of potentialeffector molecules for posttranscriptional gene silencing are available,including short hairpin RNAs (shRNAs), long dsRNAs, short temporal RNAs,and micro RNAs (miRNAs). These effector molecules either are processedinto siRNA, such as in the case of shRNA, or directly aid genesilencing, as in the case of miRNA. The present invention thusencompasses the use of shRNA as well as any other suitable form of RNAto effect posttranscriptional gene silencing by RNAi. Use of shRNA hasthe advantage over use of chemically synthesized siRNA in that thesuppression of the target gene is typically long-term and stable. AnsiRNA may be chemically synthesized, may be produced by in vitro bytranscription, or may be produced within a host cell from expressedshRNA.

In one embodiment, a siRNA is a small hairpin (also called stem loop)RNA (shRNA). These shRNAs are composed of a short (e.g., 19-25nucleotides) antisense strand, followed by a 5-9 nucleotide loop, andthe complementary sense strand. Alternatively, the sense strand mayprecede the nucleotide loop structure and the antisense strand mayfollow. These shRNAs may be contained in plasmids, retroviruses, andlentiviruses.

As used herein, “gene silencing” induced by RNA interference refers to adecrease in the mRNA level in a cell for a target gene by at least about5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%,about 70%, about 80%, about 90%, about 95%, about 99%, about 100% of themRNA level found in the cell without introduction of RNA interference.In one preferred embodiment, the mRNA levels are decreased by at leastabout 70%, about 80%, about 90%, about 95%, about 99%, about 100%.

The term “reduced” or “reduce” as used herein generally means a decreaseby at least 10% as compared to a reference level, for example a decreaseby at least about 20%, or at least about 30%, or at least about 40%, orat least about 50%, or at least about 60%, or at least about 70%, or atleast about 80%, or at least about 90% or up to and including a 100%decrease, or any integer decrease between 10-1⁰⁰% as compared to areference level.

The term “increased” or “increase” as used herein generally means anincrease of at least 1% as compared to a reference level, for example anincrease of at least about 20%, or at least about 30%, or at least about40%, or at least about 50%, or at least about 60%, or at least about70%, or at least about 80%, or at least about 90% or up to and includinga 100% increase or any integer increase between 10-100% as compared to areference level, or about a 2-fold, or about a 3-fold, or about a4-fold, or about a 5-fold or about a 10-fold increase, or any increasebetween 2-fold and 10-fold or greater as compared to a reference level.

Immunoresponsive Cells

In some embodiments, the disclosure provides immunoresponsive cells,including T cells, cytotoxic T cells, tumor-infiltrating lymphocytes(TIL), regulatory (CD4) T cells, and Natural Killer (NKT) cells,expressing at least one of an antigen-recognizing receptor. In anyaspect, the immunoresponsive cells express at least one tumor specificantigen-recognizing receptor. In some aspects, tumor cell antigenspecific T cells, NKT cells, TIL, CTL cells or other immunoresponsivecells are used. Non-limiting examples of immunoresponsive cells includeT cells, such as, for example, αβ-TCR+ T cells (e.g., CD8+ T cells orCD4+ T cells) γδ-TCR+ T cells, tumor-infiltrating lymphocytes (TIL),Natural Killer T cells (NKT), a cytotoxic T lymphocytes (CTL), and a CD4T cells.

Nucleic Acid Compositions

In some embodiments, the disclosure provides isolated nucleic acidsencoding shRNA sequences comprising a sequence at least 12, 15, 20 or 25contiguous nucleotides complementary to a nucleic acid sequence selectedfrom the group consisting of SEQ ID NOs: 604-620 and 653-678. The shRNAalso includes the reverse complement of the contiguous nucleotidesequence and a short sequence located between the two sequences so thatthe two sequences form a stem loop shRNA that can be processed within acell provide an siRNA that inhibits the expression of the proteinencoded by one of SEQ ID NOs: 604-620 and 653-678, and compositionsthereof.

Table 1 provides a list of genes identified here as being involved withtumor immunosuppression of T cells.

TABLE 1 Human Murine Sequence Sequence Accession Accession GeneHuman Gene Sequence No. No. Ppp2r2dgtgtccggccaagcggcgccctgaaggcgtgtccggccgcagcttaggctctccgg NM_ NM_gagtccccggagagtaggggcggccggcggcgctagtcttctggggagcgccgg 018461 026391gtgcacaccggaccactgcgggaggcctagggccgagggccgaggagctggcctgcgcccggcgaccccggcttccctccgcagtcgcccaggcgtcccttcccccctacagccgagcggcgccgggcgcaggcgcattgggcgcccccggcagcccccgcggcccgccccgtccgctgcccgtccgaggaggcggagggcgatgacgtcatcgagcggggcgacgggcattgggcgccattttgaaaagggaaaaaaatccctccccggcggcggcggcggcggcggcggcgccggcggtggtggcggccccggggctgagcgctcggctgcagcggcgcggaggccgtctccctggtctgccgcggtccccgcccgtcccgccgccggctgccatggcaggagccggaggcggcggctgccccgcgggcggcaacgacttccagtggtgcttctcgcaggtcaagggggccatcgacgaggacgtggccgaagcggacatcatttccaccgttgagtttaattactctggagatcttcttgcaacaggagacaagggcggcagagttgttatttttcagcgtgaacaagagaataaaagccgccctcattctaggggagaatataatgtttacagcacctttcaaagtcatgaaccggagtttgactatttgaaaagtctagaaattgaggaaaaaattaataaaattaggtggttaccacaacagaatgctgctcattttcgactgtctacaaaggataaaactataaaattatggaaaataagtgaacgggataaaagagcagaaggttataacctgaaagacgaagatggaagacttcgagacccatttaggatcacggcgctacgggtcccaatattgaagcccatggatcttatggtagaagcgagtccacggcgaatttttgcaaatgctcacacatatcatataaattccatttcagtaaatagtgatcatgaaacatatctttctgcagatgacctgtgaattaatttatggcacttagaaatcacagatagaagctttaacatcgtggacatcaagcctgctaacatggaggagctgaccgaagtcatcactgcagccgagttccacccgcaccagtgcaacgtgttcgtctacagcagtagcaaagggaccatccgcctgtgtgacatgcgctcctcggccctgtgcgacagacactccaagttttttgaagagcctgaagatcccagcagtaggtccttcttctcagaaataatttcatccatatccgatgtaaaattcagtcatagtgggcggtacatgatgaccagagactacctgtcggtgaaggtgtgggacctcaacatggagagcaggccggtggagacccaccaggtccacgagtacctgcgcagcaagctctgctctctctatgagaacgactgcatctttgacaagtttgagtgttgctggaacggttcggatagcgccatcatgaccgggtcctataacaacttcttcaggatgtttgatagagacacgcggagggatgtgaccctggaggcctcgagagagagcagcaaaccgcgcgccagcctcaaaccccggaaggtgtgtacggggggtaagcggaggaaagacgagatcagtgtggacagtctggacttcaacaagaagatcctgcacacagcctggcaccccgtggacaatgtcattgccgtggctgccaccaataacttgtacatattccaggacaaaatcaactagagacgcgaacgtgaggaccaagtcttgtcttgcatagttaagccggacatttttctgtcagagaaaaggcatcattgtccgctccattaagaacagtgacgcacctgctacttcccttcacagacacaggagaaagccgcctccgctggaggcccggtgtggttccgcctcggcgaggcgcgagacaggcgctgctgctcacgtggagacgctctcgaagcagagttgacggacactgctcccaaaaggtcattactcagaataaatgtatttatttcagtccgagccttcctttccaatttatagaccaaaaaattaacatccaagagaaaagttattgtcagataccgctctttctccaactttccctctttctctgccatcacacttgggccttcactgcagcgtggtgtggccaccgtccgtgtcctctcggccttcctccgagtccaggtggactctgtggatgtgtggatgtggcccgagcaggctcaggcggccccactcacccacagcatccgccgccaccccttcgggtgtgagcgctcaataaaaacaacacactataaagtgtttttaaatccaaaaaaaaaaaaaaa (SEQ ID NO: 604) Eif2ak3ggaaagtccaccttccccaacaaggccagcctgggaacatggagtggcagcggcc NM_ NM_gcagccaatgagagagcaaacgcgcggaaagtttgctcaatgggcgatgtccgag 004836.5010121.2 ataggagtcactcaggtggcagcggcagaggccgggctgagacgtggccaggggaacacggctggctgtccaggccgtcggggcggcagtagggtccctagcacgtccttgccttcttgggagctccaagcggcgggagaggcaggcgtcagtggctgcgcctccatgcctgcgcgcggggcgggacgctgatggagcgcgccatcagcccggggctgctggtacgggcgctgctgagctgctgctgctgctggggctcgcggcaaggacggtggccgcggggcgcgcccgtggcctcccagcgccgacggcggaggcggcgacggcctcggggcggccgctgctcccacctcagcgacgcgagtaccggcggcgggcgccgtggctgcggccgaggtgactgtggaggacgctgaggcgctgccggcagcgcgggagagcaggagctcggggtccggaaccagacgatgagacagagttgcgaccgcgcggcaggtcattagtaattatcagcactttagatgggagaattgctgccttggatcctgaaaatcatggtaaaaagcagtgggatttggatgtgggatccggttccaggtgtcatccagccttagcaaaccagaggtatttgggaataagatgatcattccttccctggatggagccctcttccagtgggaccaagaccgtgaaagcatggaaacagttcctttcacagttgaatcacttcttgaatcttcttataaatttggagatgatgttgattggaggaggaaaatctctgactacatatggactcagtgcatatagtggaaaggtgaggtatatctgacagctagggttgtcgccaatgggatagtgacgaaatggaacaagaggaagacatcctgcttctacagcgtacccaaaaaactgttagagctgtcggacctcgcagtggcaatgagaagtggaatttcagtgttggccactttgaacttcggtatattccagacatggaaacgagagccggatttattgaaagcacctttaagcccaatgagaacacagaagagtctaaaattatttcagatgtggaagaacaggaagctgccataatggacatagtgataaaggtttcggttgctgactggaaagttatggcattcagtaagaagggaggacatctggaatgggagtaccagttttgtactccaattgcatctgcctggttacttaaggatgggaaagtcattcccatcagtctttttgatgatacaagttatacatctaatgatgatgttttagaagatgaagaagacattgtagaagctgccagaggagccacagaaaacagtgtttacttgggaatgtatagaggccagctgtatctgcagtcatcagtcagaatttcagaaaagtttccttcaagtcccaaggctttggaatctgtcagtaatgaaaacgcaattattcctttaccaacaatcaaatggaaacccttaattcattctccttccagaactcctgtcttggtaggatctgatgaatttgacaaatgtctcagtaatgataagttttctcatgaagaatatagtaatggtgcactttcaatcttgcagtatccatatgataatggttattatctaccatactacaagagggagaggaacaaacgaagcacacagattacagtcagattcctcgacaacccacattacaacaagaatatccgcaaaaaggatcctgttcttcttttacactggtggaaagaaatagttgcaacgattttgttttgtatcatagcaacaacgtttattgtgcgcaggcttttccatcctcatcctcacaggcaaaggaaggagtctgaaactcagtgtcaaactgaaaataaatatgattctgtaagtggtgaagccaatgacagtagctggaatgacataaaaaactctggatatatatcacgatatctaactgattttgagccaattcaatgcctgggacgtggtggctttggagttgtttttgaagctaaaaacaaagtagatgactgcaattatgctatcaagaggatccgtctccccaatagggaattggctcgggaaaaggtaatgcgagaagttaaagccttagccaagcttgaacacccgggcattgttagatatttcaatgcctggctcgaagcaccaccagagaagtggcaagaaaagatggatgaaatttggctgaaagatgaaagcacagactggccactcagctctcctagcccaatggatgcaccatcagttaaaatacgcagaatggatcctttcgctacaaaagaacatattgaaatcatagctccttcaccacaaagaagcaggtctttttcagtagggatttcctgtgaccagacaagttcatctgagagccagttctcaccactggaattctcaggaatggaccatgaggacatcagtgagtcagtggatgcagcatacaacctccaggacagttgccttacagactgtgatgtggaagatgggactatggatggcaatgatgaggggcactcctttgaactttgtccttctgaagcttctccttatgtaaggtcaagggagagaacctcctcttcaatagtatttgaagattctggctgtgataatgcttccagtaaagaagagccgaaaactaatcgattgcatattggcaaccattgtgctaataaactaactgctttcaagcccaccagtagcaaatcttcttctgaagctacattgtctatttctcctccaagaccaaccactttaagtttagatctcactaaaaacaccacagaaaaactccagcccagttcaccaaaggtgtatctttacattcaaatgcagctgtgcagaaaagaaaacctcaaagactggatgaatggacgatgtaccatagaggagagagagaggagcgtgtgtctgcacatcttcctgcagatcgcagaggcagtggagtttcttcacagtaaaggactgatgcacagggacctcaagccatccaacatattctttacaatggatgatgtggtcaaggttggagactttgggttagtgactgcaatggaccaggatgaggaagagcagacggttctgaccccaatgccagcttatgccagacacacaggacaagtagggaccaaactgtatatgagcccagagcagattcatggaaacagctattctcataaagtggacatcttttctttaggcctgattctatttgaattgctgtatccattcagcactcagatggagagagtcaggaccttaactgatgtaagaaatctcaaatttccaccattattactcagaaatatccttgtgagtacgtgatggttcaagacatgctctctccatcccccatggaacgacctgaagctataaacatcattgaaaatgctgtatttgaggacttggactttccaggaaaaacagtgctcagacagaggtctcgctccttgagttcatcgggaacaaaacattcaagacagtccaacaactcccatagccctttgccaagcaattagccttaagttgtgctagcaaccctaataggtgatgcagataatagcctacttcttagaatatgcctgtccaaaattgcagacagtccaacaactcccatagccctttgccaagcaattagccttaagttgtgctagcctggatttgggggcataacctaatttgagccaactcctgagttttgctatacttaaggaaagggctatctttguctttgttagtctcugaaactggctgctggccaagctttatagccctcaccatttgcctaaggaggtagcagcaatccctaatatatatatatagtgagaactaaaatggatatatttttataatgcagaagaaggaaagtccccctgtgtggtaactgtattgttctagaaatatgctttctagagatatgatgattttgaaaagatttctagaaaaagctgactccatttttgtccctggcgggtaaattaggaatctgcactattttggaggacaagtagcacaaactgtataacggtttatgtccgtagttttatagtcctatttgtagcattcaatagctttattccttagatggttctagggtgggtttacagctttttgtacttttacctccaataaagggaaaatgaagctttttatgtaaattggttgaaaggtctagttttgggaggaaaaaagccgtagtaagaaatggatcatatatattacaactaacttcttcaactatggactttttaagcctaatgaaatcttaagtgtcttatatgtaatcctgtaggttggtacttcccccaaactgattataggtaacagtttaatcatctcacttgctaacatgtttttatttttcactgtaaatatgtttatgttttatttataaaaattctgaaatcaatccatttgggttggtggtgtacagaacacacttaagtgtgttaacttgtgacttctttcaagtctaaatgatttaataaaactttttttaaattaaaaaaaaaaaaaaaaaaa (SEQ ID NO: 605) Arhgap5ctcggtgagcgcgccgaggaagagaggcgagcggagagtggaggaggaggcg NM_ NM_gcggcggcgggagcggtccccaggaatgtcgctgccgccgccaccgccggggc 001030055.1009706.2 cgctgccgttgaggaggagacggaggagaccgacgttgttaggaagatgatccctatgatcttgaagatgtttctgcacagaaatgagggaaatacaaagaaccaaatacagttctgaaatttgggatctgtattttgagatgattttattttcagaatgagaagcatatctggttacctttatgaatgtagagacatgagaagagagttatgatggcaaaaaacaaagagcctcgtcccccatcctataccatcagtatagttggactctctgggactgaaaaagacaaaggtaactgtggagttggaaagtcttgtttgtgcaatagatttgtacgctcaaaagcagatgaatattatccagagcatacttctgtgcttagcaccattgactttggaggacgagtagtaaacaatgatcactttttgtactggggtgacataatacaaaatagtgaagatggagtagaatgcaaaattcatgtcattgaacaaacagagttcattgatgaccagactttcttgcctcatcggagtacgaatttgcaaccatatataaaacgtgcagctgcatctaaattgcagtcagcagaaaaactaatgtacatttgcactgatcagctaggcttagaacaagactttgaacagaagcaaatgcctgaagggaagctcaacgtagatggatttttattatgcattgatgtaagtcaaggatgcaataggaagtttgatgatcaacttaaatttgtgaataacctttttgtccagttatcaaaatcaaaaaaacctgtaataatagcagcaactaaatgtgatgaatgcgtggatcattatcttagagaagttcaggcatttgcttcaaataaaaagaaccttcttgtagtggaaacatcagcacgatttaatgtcaacattgaaacatgttttactgcactggtacaaatgttggataaaactcgtagcaagcctaaaattattccctatttggatgcttataaaacacagagacaacttgttgtcacagcaacagataagtttgaaaaacttgtgcagactgtgagagattatcatgcaacttggaaaactgttagtaataaattaaaaaatcatcctgattatgaagaatacatcaacttagagggaacaagaaaggccagaaatacattctcaaaacatatagaacaacttaaacaggaacatataagaaaaaggagagaagagtatataaatactttaccaagagctttcaacactcttttgccaaatctagaagagattgaacatttgaattggtcagaagctttgaagttaatggaaaagagagcagatttccagttatgttttgtggtgctagttaaaaactccttgggatgaaactgaccatatagacaaaattaatgataggcggattccatttgacctcctgagcactttagaagctgaaaaagtctatcagaaccatgtacagcatctgatatccgagaagaggagggtggaaatgaaggaaaaattcaaaaagactttggaaaaaattcaattcatttcaccagggcagccatgggaggaagttatgtgctttgttatggaggatgaagcctacaaatatatcactgaggctgatagcaaagaggtatatggtaggcatcagcgagaaatagttgaaaaagccaaagaagagtttcaagaaatgctttttgagcattctgaacttttttatgatttagatcttaatgcaacacctagttcagatttaaatgagtgaaattcatacagttctgagtgaagaacctagatataaagctttacagaaacttgcacctgatagggaatcccttctacttaagcatataggatttgtttatcatcccactaaagaaacatgtcttagtggccaaaattgtacagacattaaagtggagcagttacttgctagtagtcttttacagttggatcatggccgcttaagattatatcacgatagtaccaatatagataaagttaacctttttattttagggaaggatggccttgcccaagaactagcaaatgagataaggacacaatccactgatgatgagtatgccttagatggaaaaatttatgaacttgatatcggccggttgatgccaaatcgccttactttttgagtcagttatggactgccgcctttaaaccacatgggtgcttctgtgtatttaattccattgagtcattgagttttattggggaatttattgggaaaataagaactgaagcttctcagatcagaaaagataaatacatggctaatcttccatttacattaattctggctaatcagagagattccattagtaagaatctaccaattctcaggcaccaagggcagcagttggcaaacaagttgcaatgtccttttgtagatgtacctgctggtacatatcctcgtaaatttaatgaaacccaaataaagcaagctctcagaggagtattggaatcagttaaacacaatttggatgtggtgagcccaattcctgccaataaggacttatcagaagctgttccttgagaattgtcatgtgcgccatgtgtggagatccatttagtgtggatcttattctttcacccttccttgattctcattcttgcagtgctgctcaagctggacagaataattccctaatgcttgataaaatcattggtgaaaaaaggaggcgaatacagatcacaatattatcataccactcttcaattggagtaagaaaagatgaactagttcatgggtatatattagtttactctgcaaaacggaaagcttcgatgggaatgcttcgagcatttctatcagaagttcaagacaccattcctgtacagctggtggcagttactgacagccaagcagatttttttgaaaatgaggctatcaaagagttaatgactgaaggagaacacattgcaactgagatcactgctaaatttacagcactgtattctttatctcagtatcatcggcaaactgaggtctttactctgttttttagtgatgttcagagaaaaaaaatatgatagaaaattcttatttgtctgataatacaagggaatcaacccatcaaagtgaagatgtttttctaccatctcccagagactgttttccctataataactaccctgattcagatgatgacacagaagcaccacctccttatagtccaattggggatgatgtacagttgcttccaacacctagtgaccgttccagatatagattagatttggaaggaaatgagtatcctattcatagtaccccaaactgtcatgaccatgaacgcaaccataaagtgcctccacctattaattcctaaaccagttgtacctaagacaaatgtgaaaaaactcgatccaaaccttttaaaaacaattgaagctggtattggtaaaaatccaagaaagcagacttcccgggtgcctttggcacatcctgaagatatggatccttcagataactatgcggttacccattgatacaattttcaaacagaagggctattctgatgagatttatgttgtcccagatgatagtcaaaatcgtattaaaattcgaaactcatttgtaaataacacccaaggagatgaagaaatttgggttttctgatagaacctcaaaaagtcatggggaacggaggccttcaaaatacaaatataaatctaaaaccttgtttagtaaagccaagtcatactatagaagaacacattcagatgccagtgatgatgaggctttcaccacttctaaaacaaaaagaaaaggaagacatcgtggaagtgaagaagatccacttctttctcctgttgaaacttggaaaggtggtattgataatcctgcaatcacttctgaccaggagttagatgataagaagatgaagaagaaaacccacaaagtgaaagaagataaaaagcagaaaaagaaaactaagaacttcaatccaccaacacgtagaaattgggaaagtaattactttgggatgcccctccaggatctggttacagctgagaagcccataccactatttgttgagaaatgtgtggaatttattgaagatacagggttatgtaccgaaggactctaccgtgtcagcgggaataaaactgaccaagacaatattcaaaagcagtttgatcaagatcataatatcaatctagtgtcaatggaagtaacagtaaatgctgtagctggagcccttaaagctttctttgcagatctgccagatcctttaattccatattctcttcatccagaactattggaagcagcaaaaatcccggataaaacagaacgtcttcatgccttgaaagaaattgttaagaaatttcatcctgtaaactatgatgtattcagatacgtgataacacatctaaacagggttagtcagcaacataaaatcaacctaatgacagcagacaacttatccatctgtttttggccaaccttgatgagacctgattttgaaaatcgagagtttctgtctactactaagattcatcaatctgttgttgaaacattcattcagcagtgtcagtttttcttttacaatggagaaattgtagaaacgacaaacattgtggctcctccaccaccttcaaacccaggacagttggtggaaccaatggtgccacttcagttgccgccaccattgcaacctcagctgatacaaccacaattacaaacggatcctcttggtattatatgagtaggaagtgattgcaaacaggctggatttggacaaaaagcaaatctagacatgcatgtttcagggttcagtagtatacttcatgtttcatacagataattcacattcaaaattacattttctctttgaactagatggtattccttattcacttacattacaaatctaagaccatgtgataagcatgactggagaggtttaatttttataaacaaaaatagctataaagtacaaagctgctgctgcatgcaaccttattgcaatcagtatatcattcctgtggcaatttctgtcaccttatattgtgaataaaatttttctatagaaattaaatgatttaaaaactcacctatatgaaacatttaatgcttttcagcctgctttctggctgattttgttatttgatgtgctaatttgggcaacttaatttacattctggcagtcggtgtagataactaaaagcccagttaagtattttataatttcaggctactgaggccatgcttgggatgttgtttgaaagaaagaaaaaatacacttgacatatttcacatttctgtaccttcatctttacttccaagtaaacccgtggatgatttgatgagggataaatgaacctatttcttttttcacacataccaaggacatgcttgtggctaaagtgagttgataatgttgtgcaaaggatagttgtcaccaactcatttctttatggtccataatgttaataaaaattttgtatactgttaattctgtaaacagatgcatgttcaaaagatctatgatggtcttgtaatcttaatctaatatattttagatattttaattttttccctatggggaacacatttagtatagtgtagaaaatactccatgacattttcatataaggttatataacttttcatacataaacatgaaatttgttgtagaaaattctttaaaccaaacatttaaatctaggacttcaatttaatttgttccttgaatctatttttatgtggcccttaaaaaatatccaaaaaacccaagctaatatagcaataaaaatactttgggtactgacagactctttggagtgtttatattacaaatttgtattcatattcttttctgtgatgtgttgtactaaaatccaaaatggcttttgcaccatttttaagccaattttttcctttgatgttggtaccagaattactataagtgactgctgcttttgggggtaaacattttgttagtgaagataaaaccagaacactaaattatggataaaattttcagaataggtggcacaggtaaatttcactaggttatattttgtgtagtaaagaaaaaaattatttggtcaatgttatcttaattcatactacaatttaagattatcttatgtgtattatagtaaatagatgattttcagattcaaggctcctaagagtttgatttgctctgttttttcctaaaataaatattgtctctcccaactgttaagttctaggtattgtacttccaattttaacttcagaaccaagatgttggcatgaaccaggctgctgttgaagtacatgtatattataaattatcttatttgtgttatactcttacatgttatcttttaaagaaaacaaagtccctattattcctattgcaaagcacacaggaattaagaaagtacagtaatttttaaaaaaaaatccggtaaatgtagtattcttaacctgttctatattacttatacctattgtctatatagctttaatttatagttgtcagtttaactattggcatgtctggcaaagaaaattaaactttaagagttttataaactgtttctaggttgctaaagaatttatttttctactatatatggtatagacaaagcatcaaactatgtacaggaaaaaagcctgactatttctatttggaagtaggctgaaaagagaattttcaaaactgttcgtgtcttcagttcattctgtcataactttgctattgtaatatgtgaataccagtttatttaagctgttctcttttatactgtattaatttaatgttcatctgcgtttagtaccatttttgttattaaaactggcatttaccgtttttcacattaacccaccttgcaccttcccccaaacttatctccacttttctatgcattctatcattgatttgacacacttcatagtcagtcatttaaatactctacgtttggttcaattaaccagtaggttacagttattgaaaattaaagtacagtttaaagctcagtctgttacactgaattgattgtgtttgtttttgccaagggtttagatatgcttttaaatattagaaacatctaagaacagaataacataattaaacttttttctggtaagttactggaaggtttcactgtttaggcacctatcatatgagacttcttaaaggattaaaagaataggatagtctcataattgtgagtaaacatcaaggcattatattttacaatactgaataaaatttcatctacacacatgttgccattgtttcatttaaggttcagtgcttatagttaactacaatattggacctaacaggatctagattagcaatataaagaagcatagtggtactctgtttcacactttcagtagatttattagaagtcaaattctattcaacagacacttattaggatatacaactaatttaagaataaaattccaggcacaatatattttttttaaatggtatttgttagtagtgcttcttccccttaacatttacagtgtaaatactgcaggtaaccgcaatctaagttagccaaaaagcagctttttttcccatactgtatgtaaataatgtagacctgggtttttttgtttatttgggtttgtttttttttttgaggtactggaatctaattaatatctcttaggtatcaacaaaagggaacaattggaatgagaatttaggccttagcttccatggtgatttttagttttttatacagtaataattgtgatgctatttgtcaactggatataaatacacatataattttaaaaagtcaaaagtgcttttgtttctttgtttaatgtaatttttgtgcttcacctacaggatgctgcagtaaattaaatatcagtgaagcttctgatgtataaagaatgctatgaataaaacattaagaagctgtgtaattttaagttatagttgcctctatttttaccatttcattggtaaaaattagctaatttttttcaagtgaaatgaaaaataaaaatataaatttatcaatatgatggaaatcttattaaggagatgtattattgaattttcactgtacctgaaaaggagattcaaaattttttctggggatgtatataggtgaaaatttgattttttaaattatcaggaaaacaagataatgcacagatttctaagactaagatcttacctggatgtgatttttgagctgtggctagacattctttagagccactggaaatattttgaaaactattctagttatagcagagctgctaatattaacgaatatatttgtgtcttcatggtttgtgactattaggccaaattttgtggtatatgttgtcagtctggatctggtgaggtctgttcaacatgaatctttgtgttatcttgaatttagtagtttcaaggtacttaaattcttaacagtttctaatttgtttcaatacatatgggacatggttgatttttttactgtattagaactcttggaagttcttagccttttcaggttatgaaatacctgaaagtaaaattttctaagatttaataagggaagatactattcaaatcattttcttaggatagcatctttacatacaatgagaggattgtacaagcattaatctcatattccaacatccagttacttgatgtgatccaagtaccctggtctttttgaagcagttaaaatctaattaattaactttgggagtcttcactattcaattgatcctcatcattgtcctatttgcatgactccattttttcctccactatatgagttttctttgtcagggggagaggagtgggaagagtcacagaatctcatattcacatcttaattaaattgtgtgaaattagtcttttgtggaaattctgtaggcagtatgattttgaaaagctaaccaatgataattagcattttagttaatactaaatgcataaaattataacccttgaaattaatttggtgctggcagttctggtttagtcatttttaccagtagttagtagtattaagacctgcagtatatgcactttttgagtagctgtcaaataattgtagttgagaaacaacttgtttattctcacaattcagattttctattcagttttgtctcaaatagtaagttattgtgaacaatttaataacggccctcctgttctagtttgcctaatattttagttaagatttagtgttttaacctatttttttaagtttattttttgtattagattttatttgaataagttatgtgggtttagtaattgacctatttattcattgcttcactaattcatccagattagttttaagtgtgtatatgtatttgctcaccagatcattttcttgggaccttgaactgtgaatgttttgtcctaaccatttaatattttctaggtacttgctgcaagttcttgaactattttaccagctttaactttggggctcttagtttcttttctccagattcttgttattttattttatccaaataaatatttaggtgttctaagaa (SEQ ID NO: 606) Smad2cggccgggaggcggggcgggccgtaggcaaagggaggtggggaggcggtggc NM_ NM_cggcgactccccgcgccccgctcgccccccggcccttcccgcggtgctcggcctc 001003652001252481 gttcctttcctcctccgctccctccgtcttccatacccgccccgcgcggctttcggccggcgtgcctcgcgccctaacgggcggctggaggcgccaatcagcgggcggcagggtgccagccccggggctgcgccggcgaatcggcggggcccgcggcccagggtggcaggcgggtctacccgcgcggccgcggcggcggagaagcagctcgccagccagcagcccgccagccgccgggaggttcgatacaagaggctgttttcctagcgtggcttgctgcctttggtaagaacatgtcgtccatcttgccattcacgccgccagttgtgaagagactgctgggatggaagaagtcagctggtgggtctggaggagcaggcggaggagagcagaatgggcaggaagaaaagtggtgtgagaaagcagtgaaaagtctggtgaagaagctaaagaaaacaggacgattagatgagcttgagaaagccatcaccactcaaaactgtaatactaaatgtgttaccataccaagcacttgctctgaaatttggggactgagtacaccaaatacgatagatcagtgggatacaacaggcctttacagcttctctgaacaaaccaggtctcttgatggtcgtctccaggtatcccatcgaaaaggattgccacatgttatatattgccgattatggcgctggcctgatcttcacagtcatcatgaactcaaggcaattgaaaactgcgaatatgcttttaatcttaaaaaggatgaagtatgtgtaaacccttaccactatcagagagttgagacaccagttttgcctccagtattagtgccccgacacaccgagatcctaacagaacttccgcctctggatgactatactcactccattccagaaaacactaacttcccagcaggaattgagccacagagtaattatattccagaaacgccacctcctggatatatcagtgaagatggagaaacaagtgaccaacagttgaatcaaagtatggacacaggctctccagcagaactatctcctactactctttcccctgttaatcatagcttggatttacagccagttacttactcagaacctgcattttggtgttcgatagcatattatgaattaaatcagagggttggagaaaccttccatgcatcacagccctcactcactgtagatggctttacagacccatcaaattcagagaggttctgcttaggtttactctccaatgttaaccgaaatgccacggtagaaatgacaagaaggcatataggaagaggagtgcgcttatactacataggtggggaagtttttgctgagtgcctaagtgatagtgcaatctttgtgcagagccccaattgtaatcagagatatggctggcaccctgcaacagtgtgtaaaattccaccaggctgtaatctgaagatcttcaacaaccaggaatttgctgcttcttctggctcagtctgttaatcagggttttgaagccgtctatcagctaactagaatgtgcaccataagaatgagttttgtgaaagggtggggagcagaataccgaaggcagacggtaacaagtactccttgctggattgaacttcatctgaatggaaagcatgtcataaagcttcaccaatcaagtcccatgaaaagacttaatgtaacaactcttctgtcatagcattgtgtgtggtccctatggactgtttactatccaaaagttcaagagagaaaacagcacttgaggtctcatcaattaaagcaccttgtggaatctgtttcctatatttgaatattagatgggaaaattagtgtctagaaatactctcccattaaagaggaagagaagattttaaagacttaatgatgtcttattgggcataaaactgagtgtcccaaaggtttattaataacagtagtagttatgtgtacaggtaatgtatcatgatccagtatcacagtattgtgctgtttatatacatttttagtttgcatagatgaggtgtgtgtgtgcgctgcttcttgatctaggcaaacctttataaagttgcagtacctaatctgttattcccacttctctgttatttttgtgtgtcttttttaatatataatatatatcaagattttcaaattatttagaagcagattttcctgtagaaaaactaatttttctgccttttaccaaaaataaactcttgggggaagaaaagtggattaacttttgaaatccttgaccttaatgtgttcagtggggcttaaacagtcattctttttgtggttttttgtttttttttgtttttttttttaactgctaaatcttattataaggaaaccatactgaaaacctttccaagcctcttttttccattcccatttttgtcctcataatcaaaacagcataacatgacatcatcaccagtaatagttgcattgatactgctggcaccagttaattctgggatacagtaagaattcatatggagaaagtccctttgtcttatgcccaaatttcaacaggaataattggcttgtataatctagcagtctgttgatttatccttccacctcataaaaaatgcataggtggcagtataattattttcagggatatgctagaattacttccacatatttatccctttttaaaaaagctaatctataaataccgtttttccaaaggtattttacaatatttcaacagcagaccttctgctcttcgagtagtttgatttggtttagtaaccagattgcattatgaaatgggccttttgtaaatgtaattgtttctgcaaaatacctagaaaagtgatgctgaggtaggatcagcagatatgggccatctgtttttaaagtatgttgtattcagtttataaattgattgttattctacacataattatgaattcagaattttaaaaattgggggaaaagccatttatttagcaagttttttagcttataagttacctgcagtctgagctgttcttaactgatcctggttttgtgattgacaatatttcatgctctgtagtgagaggagatttccgaaactctgttgctagttcattctgcagcaaataattattatgtctgatgttgactcattgcagtttaaacatttcttcttgtttgcatcttagtagaaatggaaaataaccactcctggtcgtcttttcataaattttcatatttttgaagctgtctttggtacttgttctttgaaatcatatccacctgtctctataggtatcattttcaatactttcaacatttggtggttttctattgggtactccccattttcctatatttgtgtgtatatgtatgtgttcatgtaaatttggttttagtaattttttattcattcaacaaatatttattgttcacctgtttgtaccaggaacttttctttgtctttgggtaaaggtgaacaagacaactacagttcctgcctttgctgagacagcagttacactaacccttaattatcttacttgtctatgaaggagataaacagggtactgtactggagaataacagatgggatgcttcaggtaggacatcaaggaaagcctctaaggaaaggatgcatgagctaacacctgacattaaagaagcaagccaagtgaggagcatggggagataagatttcctggcaaagagaatagcatcaaatgcaaaaaggttcacactaaaggaaaacctgattaggtattaatgctttatacagaaacctctatacaaatccaaacttgaagatcagaatggttctacagttcataacattttgaaggtggccttattttgtgatagtctgcttcatgtgattctcactaacatatctccttcctcaacctttgctgtcaaaatttcatttgcaccacatcagtactacttaatttaacaagcttttgttgtgtaagctctcactgttttagtgccctgctgcttgcttccagactttgtgctgtccagtaattatgtcttccactacccatcttgtgagcagagtaaatgtcctaggtaataccactatcaggcctgtaggagatactcagtggagcctctgcccttctttttcttacttgagaacttgtaatggtgttagggaacagttgtaggggcagaaaacaactctgaaagtggtagaaggtcctgatcttggtggttactcttgcattactgtgttaggtcaagcagtgcctactatgctgtttcagtagtggagcgcatctctacagttctgatgcgatttttctgtacagtatgaaattgggactcaactattgaaaacacctattgagcagttatacctgttgagcagtttacttcctggttgtaattacatttgtgtgaatgtgtttgatgctttttaacgagatgatcttttttgtattttatctactgtggcctgattttttttttgttttctgcccctccccccatttataggtgtggttttcatttttctaagtgatagaatcccctctttgttgaatttttgtctttatttaaattagcaacattacttaggatttattcttcacaatactgttaattttctaggaatgatgacctgagaaccgaatggccatgctttctatcacatttctaagatgagtaatattttttccagtaggttccacagagacaccttgggggctggcttaggggaggctgttggagttctcactgacttagtggcatatttattctgtactgaagaactgcatggggtttcttttggaaagagtttcattgctttaaaaagaagctcagaaagtctttataaccactggtcaacgattagaaaaatataactggatttaggcctaccttctggaataccgctgattgtgctctttttatcctactttaaagaagctttcatgattagatttgagctatatcagttataccgattataccttataatacacattcagttagtaaacatttattgatgcctgttgtttgcccagccactgtgatggatattgaataataaaaagatgactaggacggggccctgacccttgagctgtgcttggtcttgtagaggttgtgttttttttcctcaggacctgtcactttggcagaaggaaatctgcctaatttttcttgaaagctaaattttctttgtaagtttttacaaattgtttaatacctagttgtattttttaccttaagccacattgagttttgcttgatttgtctgtcttttaaacactgtcaaatgctttcccttttgttaaaattattttaatttcactttttttgtgcccttgtcaatttaagactaagaccttgaaggtaaaacaaacaaacaaacatcagtcttagtctcttgctagttgaaatccaataaaagaaaatatatacccagttggtttctctacctcttaaaagcttcccatatatacctttaagatccttctcttttttctttaactactaaataggttcagcatttattcagtgttagataccctcttcgtctgagggtggcgtaggtttatgttgggatataaagtaacacaagacaatcttcactgtacataaaatatgtcttcatgtacagtctttactttaaaagctgaacattccaatttgcgccttccctcccaagcccctgcccaccaagtatctctttagatatctagtctgtggacatgaacaatgaatacttttttcttactctgatcgaaggcattgatacttagacatatcaaacatttcttcctttcatatgctttactttgctaaatctattatattcattgcctgaattttattcttcctttctacctgacaacacacatccaggtggtacttgctggttatcctctttcttgttagccttgttttttgttttttttttttttttttgagagggagtctcgctctgttgcccaacctggagtgcagtggtgcgatcttggttcactgcaagctccgcctcccgggttcacgccatgcttctgcctcagcctcccaagtagctgggactacaggcgcccaccaccacactcggctaattttttgtatttttagtagagacggggtttcaccgtgttggccaggatggtctcgatctcctgacctcgtgatctgtccacctcggcttcccaaagtgctgggattacaggcatgagccaccgcgcccagcctagccatatttttatctgcatatatcagaatgtttctctcctttgaacttattaacaaaaaaggaacatgcttttcatacctagagtcctaatttcttcatcatgaaggttgctattcaaattgatcaatcattttaattttacaaatggctcaaaaattctgttcagtaaatgtctttgtgactggcaaatggcataaattatgtttaagattatgaacttttctgacagttgcagccaatgttttccctacgataccagatttccatcttggggcatattggattgttgtatttaagacagtcagaataatgatagtgtgtggtctccagaggtagtcagaatcctgctattgagttctttttatatcttccttttcaattttttattaccattttgtttgtttagactacacttgtagggattgaggggcaaattatctcttggagtggaattcctgtgttttgagccttacaaccaggaaatatgagctatactagatagcctcatgatagcatttacgataagaacttatctcgtgtgttcatgtaattttttgagtaggaactgttttatcttgaatattgtagctaactatatatagcagaactgcctcagtctttttaagaaggaaataaataatatatgtgtatgaatttatatatacatatacactcatagacaaacttaacagttggggtcattctaacagttaaaacaattgttccattgtttaaatctcagatcctggtaaaatgttcttaatttgtctgtgtttcattttcctttcatggacagaccattggagtacattaattttcttaatctgccatttggcagttcatttaatataccattttttggcaacttggtaactaagaatcacagccaaaatttgttaacatcaaagaaagctctgccatataccccgttactaaattattatacatccagcagattagggatgtactttacttagggttaactttgttgttgttgataatactagattgctccctctttaattcttcttctggtgcaaggttgctgcttaagttaccctgggaaatactactacaaggtcaaattttctagtatcttacagcctgattgttaggtgattcagatctttgctcaatataaatggattttccaagattctctgggccatccttgacccacaggtgatctcgctggagtatattaacttaaatcagtgccagttggtttggtgccatgagatccataatgaatccagaacttcaccattgcttagatataagagtcccttggaagaataatgccactgatgatgggggtcagaaggtgtattaactcaacatagagggcttttagatttttcttcaaaaaaatttcgagaaaagtattcttttttccctccaaacagttaacagctcttagtttctccaaatatgctctttgatttacttatttttaattaaagatggtaatttattgaacaatgaaatccgtaatatattgatttaaggacaaaagtgaagttttagaattataaaagtacttaaatattatatattttccatttcataattgttttcctttctctgtggctttaaagtttttgactattttacaatgttaatcactaggtaacttgccatatttctggttctatattaagttctatcctttataatgctgttattataaagctggtttttagcatttgtctgtagcaatagaaattttactaagtctctgttctcccagtaagttttttcttttctcagtaagtccctaagaaaacatttgtttgccactcttactattcccaatcttggattgttcgagctgaaaaaaaatttgatgagaattcaggaggatccttttctggtgaattttaggttcctgctttaagaatgtggaaatccattgctttatataactaatatacacacagattaattaaaattgtgagaaataattcacacatgacaagtaggtaacatgcatgagttttgaatttttttaaaaacccaactgtttgacaaaatatagaacccaaattggtactttcttagaccagtgtaacctcacacctcagttttgcttttccaaccctgacttgaaaggcatatttgtatctttttattagtgatagtgaagctgtgacactaaccttttatacaaaagagtaaagaaagaaaaactacagcgattaagatgagaacagttctgcagttgttgaactagatcacagcattgtaggcagaataaaaaatgttcatatctgagaatattcctttcgccatcttttcccaaggccagacctcctggtggagcacagttaaaagtaacattctgggcctttgtaatcggagggctgtgtctccagctggcagcctttgttttaatatataatgcaggactgtggaaaacagttggcatagaatattttcacctaaaaaagaaagaaaagacatacaaaactggattaattgcaaaaagagaatacagtaaaataccatataactggacaaagctagaagaacctttagaagatttgtctgaaaacagatttcaagagtgagcttttatacaagctcactaatttgcttgattactaccaactcttcttaaagttaacacgtttaaggtatttctggacttcctagccttttagcaagcttagaggaactagccattagctagtgatgtaaaaatattttggggactgatgcccttaaaggttatgcccttgaaagttcttaccttttctctagtgatattaaggaacgagtgggtagtgttctcagggtgaccagctgccctcaagtgcctgggattgagggtttccctggatgcgggactttccctggatacaaaacttttagcagagttttgtatatatgtggatttttctgataagtagcacatcagaggccttaaccactgcccaaaagcgattctccattgagagtacatatcttgaacttaagaaattcatttgctctgatttttaatcttgtaaagtttttgctaaactcaaaacaagtcccaggcacaccagaaggagctgaccaccttaggtgttcttgtgatttatccttacttccctatgttgtcatagttgcttctaaactcagctgcactatggctgtcaacatttctgatacttattgggatatgtgccatccagtcatttagtactttgaatggaacatgagatttataacacaggtaatcgctgaaggtaccagtatggtggtgagactcacacttagtgatccagctaaggtaactgatgttataatggaacagagaagaggccaactagatagctaagttcttctgaacctatgtgtatatgtaagtacaaatcatgcgtccttatggggttaaacttaatctgaaatttacatttttcatagtaaaaggaaaccaattgttgcagatttcttttcttgtgaggaaatacatggcctttgatgctctggcgtctactgcatttcccagtctgttctgctcgagaagccagaatgtgttgttaacatttttccgtgaatgttgtgttaaaatgattaaatgcatcagccaatggcaagtgaaggaattgggtgtcctgatgcagactgagcagtttctctcaattgtagcctcatactcataaggtgcttaccagctagaacattgagcacgtgaggtgaaattttttttctctgatggcattaactttgtaatgcaatatgatggatgcagaccctgttcttgtttccctctggaagtccttagtggctgcatccttggtgcactgtgatggagatattaaatgtgttctttgtgagctttcgttctatgattgtcaaaagtacgatgtggttccttttttatttttattaaacaatgagctgaggctttattacagctggttttcaagttaaaattgttgaatactgatgtctttctcccacctacaccaaatattttagtctatttaaagtacaaaaaaagttctgcttaagaaaacattgcttacatgtcctgtgatttctggtcaatttttatatatatttgtgtgcatcatctgtatgtgctttcactttttaccttgtttgctcttacctgtgttaacagccctgtcaccgttgaaaggtggacagttttcctagcattaaaagaaagccatttgagttgtttaccatgttaaaaaaaaaaaaaaaa(SEQ ID NO: 607) Akap81gtgtgtggaggggaccctgtggttagcagcagctatcgcagcgtcggatgttcagag NM_014371NM_017476 cagcagaagccggcgtcgtcggatgttgtgttgcccgccaccatgagctacacttggctttgtccagggatctgaaaccactttgcagtcgacatactcggataccagcgctcagcccacctgtgattatggatatggaacttggaactctgggacaaatagaggctttcgagggctatggctatggctatggctatggccaggataacaccaccaactatgggtatggtatggccacttcacactcttgggaaatgcctagctctgacacaaatgcaaacactagtgcctcgggtagcgccagtgccgattccgttttatccagaattaaccagcgcttagatatggtgccgcatttggagacagacatgatgcaaggaggcgtgtacggctcaggtggagaaagctatgactcttatgagtcctgcgactcgagggccgtcctgagtgagcgcgacctgtaccggtcaggctatgactacagcgagcttgaccctgagatggaaatggcctatgagggccaatacgatgcctaccgcgaccagttccgcatgcgtggcaacgacaccttcggtcccagggcacagggctgggcccgggatgcccggagcggccggccaatggcctcaggctatgggcgcatgtgggaagaccccatgggggcccggggccagtgcatgtctggtgcctctcggctgccctccctcttctcccagaacatcatccccgagtacggcatgttccagggcatgcgaggtgggggcgccttcccgggcggctcccgctttggtttcgggtttggcaatggcatgaagcagatgaggcggacctggaagacctggaccacagccgacttccgaaccaagaagaagaagagaaagcagggcggcagtcctgatgagccagatagcaaagccacccgcacggactgctcggacaacagcgactcagacaatgatgagggcaccgagggggaagccacagagggccttgaaggcaccgaggctgtggagaagggctccagagtggacggagaggatgaggagggaaaagaggatgggagagaagaaggcaaagaggatccagagaagggggccctaaccacccaggatgaaaatggccagaccaagcgcaagttgcaggcaggcaagaagagtcaggacaagcagaaaaagcggcagcgagaccgcatggtggaaaggatccagtttgtgtgttctctgtgcaaataccggaccttctatgaggacgagatggccagccatcttgacagcaagttccacaaggaacactttaagtacgtaggcaccaagctccctaagcagacggctgactttctgcaggagtacgtcactaacaagaccaagaagacagaggagctccgaaaaaccgtggaggaccttgatggcctcatccaccaaatctacagagaccaggatctgacccaggaaattgccatggagcattttgtgaagaaggtggaggcagcccattgtgcagcctgcgacctcttcattcccatgcagtttgggatcatccagaagcatctgaagaccatggatcacaaccggaaccgcaggctcatgatggagcagtccaagaagtcctccctcatggtggcccgcagtattctcaacaacaagctcatcagcaagaagctggagcgctacctgaagggcgagaaccctttcaccgacagccccgaggaggagaaggagcaggaggaggctgagggcggtgccctggacgagggggcgcagggcgaagcggcagggatctcggagggcgcagagggcgtgccggcgcagcctcccgtgcccccagagccagcccccggggccgtgtcgccgccaccgccgccgcccccagaggaggaggaggagggcgccgtgcccttgctgggaggggcgctgcaacgccagatccgcggcatctcgggcctcgacgtggaggacgacgaggagggcggcgggggcgccccgtgacccgagctcggggcgggcggagcccgcgtggccgaagctggaaaccaaacctaataaagttttcccatcccaccaaaaaaaaaaaaaaaaaaaaaa (SEQ ID NO: 608) Rbksacctttgagcgatggcggcgtctggggaaccccagaggcagtggcaagaggaggt NM_022128NM_153196 ggcggcggtggtagtggtgggctcctgcatgaccgacctggtcagtcttacttctcgtttgccaaaaactggagaaaccatccatggacataagttttttattggctttggagggaaaggtgccaaccagtgtgtccaagctgctcggcttggagcaatgacgtccatggtgtgtaaggttggcaaagattcttttggcaatgatttatatagaaaacttaaaacagaatgatatttctacagaatttacatatcagactaaagatgctgctacaggaactgcttctataattgtcaataatgaaggccagaatatcattgtcatagtggctggagcaaatttacttttgaatacggaggatctgagggcagcagccaatgtcattagcagagccaaagtcatggtctgccagctcgaaataactccagcaacttctttggaagccctaacaatggcccgcaggagtggagtgaaaaccttgttcaatccagcccctgccattgctgacctggatccccagttctacaccctctcagatgtgttctgctgcaatgaaagtgaggctgagattttaactggcctcacggtgggcagcgctgcagatgctggggaggctgcattagtgctcttgaaaaggggctgccaggtggtaatcattaccttaggggctgaaggatgtgtggtgctgtcacagacagaacctgagccaaagcacattcccacagagaaagtcaaggctgtggataccacgggtgctggtgacagctttgtgggagctctggccttctacctggcttactatccaaatctgtccttggaagacatgctcaacagatccaatttcattgcagcagtcagtgtccaggctgcaggaacacagtcatcttacccttacaaaaaagaccttccgcttactctgttttgattgctattagtcccaaaataaatatacctgggaataaaatgtacttgggggtggctgctcctggctaatgcttattagaaaatgtcctcgtcccctttctttgcaaatttagttcttttacgaagtcatcctcaagcttcaatttatttataacgatgattcttttgctttccatgcatttgcacaaaacaaccagaattaaagattccacaacc (SEQ ID NO: 609) Egr2aactgagcgaggagcaattgattaatagctcggcgaggggactcactgactgttataa NM_000399NM_010118 taacactacaccagcaactcctggcttcccagcagccggaacacagacaggagagagtcagtggcaaatagacatttttcttatttcttaaaaaacagcaacttgtttgctacttttatttctgttgatttttttttcttggtgtgtgtggtggttgtttttaagtgtggagggcaaaaggagataccatcccaggctcagtccaacccctctccaaaacggcttttctgacactccaggtagcgagggagttgggtctccaggttgtgcgaggagcaaatgatgaccgccaaggccgtagacaaaatcccagtaactctcagtggttttgtgcaccagctgtctgacaacatctacccggtggaggacctcgccgccacgtcggtgaccatctttcccaatgccgaactgggaggcccctttgaccagatgaacggagtggccggagatggcatgatcaacattgacatgactggagagaagaggtcgttggatctcccatatcccagcagctttgctcccgtctctgcacctagaaaccagaccttcacttacatgggcaagttctccattgaccctcagtcccctggtgccagctgctacccagaaggcataatcaatattgtgagtgcaggcatcttgcaaggggtcacttccccagcttcaaccacagcctcatccagcgtcacctctgcctcccccaacccactggccacaggacccctgggtgtgtgcaccatgtcccagacccagcctgacctggaccacctgtactctccgccaccgcctcctcctccttattctggctgtgcaggagacctctaccaggacccttctgcgttcctgtcagcagccaccacctccacctcttcctctctggcctacccaccacctccttcctatccatcccccaagccagccacggacccaggtctcttcccaatgatcccagactatcctggattctttccatctcagtgccagagagacctacatggtacagctggcccagaccgtaagccctttccctgcccactggacaccctgcgggtgccccctccactcactccactctctacaatccgtactttaccctggggggccccagtgctggggtgaccggaccaggggccagtggaggcagcgagggaccccggctgcctggtagcagctcagcagcagcagcagccgccgccgccgccgcctataacccacaccacctgccactgcggcccattctgaggcctcgcaagtaccccttacagacccagcaagacgccggtgcacgagaggccctacccgtgcccagcagaaggctgcgaccggcggttctcccgctctgacgagctgacacggcacttccgaatccacactcggcataagcccttccagtgtcggatctgcatgcgcaacttcagccgcagtgaccacctcaccacccatatccgcacccacaccggtgagaagcccttcgcctgtgactactgtggccgaaagtttgcccggagtgatgagaggaagcgccacaccaagatccacctgagacagaaagagcggaaaagcagtgccccctctgcatcggtgccagccccctctacagcctcctgctctgggggcgtgcagcctgggggtaccctgtgcagcagtaacagcagcagtcttggcggagggccgctcgccccttgctcctctcggacccggacaccttgagatgagactcaggctgatacaccagctcccaaaggtcccggaggccctttgtccactggagctgcacaacaaacactaccaccctttcctgtccctctctccctttgttgggcaaagggctttggtggagctagcactgccccctttccacctagaagcaggttcttcctaaaacttagcccattctagtctctcttaggtgagttgactatcaacccaaggcaaaggggaggctcagaaggaggtggtgtggggacccctggccaagagggctgaggtctgaccctgctttaaagggttgtttgactaggttttgctaccccacttccccttattttgacccatcacaggtttttgaccctggatgtcagagttgatctaagacgttttctacaataggttgggagatgctgatcccttcaagtggggacagcaaaaagacaagcaaaactgatgtgcactttatggcttgggactgatttgggggacattgtacagtgagtgaagtatagcctttatgccacactctgtggccctaaaatggtgaatcagagcatatctagttgtctcaacccttgaagcaatatgtattataaactcagagaacagaagtgcaatgtgatgggaggaacatagcaatatctgctccttttcgagttgtttgagaaatgtaggctattttttcagtgtatatccactcagattttgtgtatttttgatgtacactgttctctaaattctgaatctttgggaaaaaatgtaaagcatttatgatctcagaggttaacttatttaagggggatgtacatatattctctgaaactaggatgcatgcaattgtgttggaagtgtccttggtgccttgtgtgatgtagacaatgttacaaggtctgcatgtaaatgggttgccttattatggagaaaaaaatcactccctgagtttagtatggctgtatatttctgcctattaatatttggaattttttttagaaagtatatttttgtatgctttgttttgtgacttaaaagtgttacctttgtagtcaaatttcagataagaatgtacataatgttaccggagctgatttgtttggtcattagctcttaatagttgtgaaaaaataaatctattctaacgcaaaaccactaactgaagttcagataatggatggtttgtgactatagtgtaaataaatacttttcaacaataaaaaaaaaaaaaaa (SEQ ID NO: 610) Dgkaagttcctgccagtgagtccctaggcctccatctctctcccttgctgtaccaccttcacca NM_001345NM_016811 ccatccatgcgaccccaagagccttaatgactctagaagagactccaggcaggggaagctgaaaggacctttcactccctacttttggccagggccttctgtgccacctgccaagaccagcaggcctaccctctgaagaggtccaagcaacggaagtactactacgaagctgcctttctggccatccttgagaaaaatagacagatggccaaggagaggggcctaataagccccagtgattttgcccagctgcaaaaatacatggaatactccaccattaaaggtcagtgatgtcctaaagctcttcgaggatggcgagatggctaaatatgtccaaggagatgccattgggtacgagggattccagcaattcctgaaaatctatctcgaagtggataatgttcccagacacctaagcctggcactgtttcaatcctttgagactggtcactgcttaaatgagacaaatgtgacaaaagatgtggtgtgtctcaatgatgtttcctgctacttttcccttctggagggtggtcggccagaagacaagttagaattcaccttcaagctgtacgacacggacagaaatgggatcctggacagctcagaagtggacaaaattatcctacagatgatgcgagtggctgaatacctggattgggatgtgtctgagctgaggccgattcttcaggagatgatgaaagagattgactatgatggcagtggctctgtctctcaagctgagtgggtccgggctggggccaccaccgtgccactgctagtgctgctgggtctggagatgactctgaaggacgacggacagcacatgtggaggcccaagaggttccccagaccagtctactgcaatctgtgcgagtcaagcattggtcttggcaaacagggactgagctgtaacctctgtaagtacactgttcacgaccagtgtgccatgaaagccctgccttgtgaagtcagcacctatgccaagtctcggaaggacattggtgtccaatcacatgtgtgggtgcgaggaggctgtgagtccgggcgctgcgaccgctgtcagaaaaagatccggatctaccacagtctgaccgggctgcattgtgtatggtgccacctagagatccacgatgactgcctgcaagcggtgggccatgagtgtgactgtgggctgctccgggatcacatcctgcctccatcttccatctatcccagtgtcctggcctctggaccggatcgtaaaaatagcaaaacaagccagaagaccatggatgatttaaatttgagcacctctgaggctctgcggattgaccctgttcctaacacccacccacttctcgtctttgtcaatcctaagagtggcgggaagcaggggcaaagggtgctctggaagttccagtatatattaaaccctcgacaggtgttcaacctcctaaaggatggtcctgagatagggctccgattattcaaggatgttcctgatagccggattttggtgtgtggtggagacggcacagtaggctggattctagagaccattgacaaagctaacttgccagttttgcctcctgttgctgtgttgcccctgggtactggaaatgatctggctcgatgcctaagatggggaggaggttatgaaggacagaatctggcaaagatcctcaaggatttagagatgagtaaagtggtacatatggatcgatggtctgtggaggtgatacctcaacaaactgaagaaaaaagtgacccagtcccctttcaaatcatcaataactacttctctattggcgtggatgcctctattgctcatcgattccacatcatgcgagagaaatatccggagaagttcaacagcagaatgaagaacaagctatggtacttcgaatttgccacatctgaatccatcttctcaacatgcaaaaagctggaggagtctttgacagttgagatctgtgggaaaccgctggatctgagcaacctgtccctagaaggcatcgcagtgctaaacatccctagcatgcatggtggctccaacctctggggtgataccaggagaccccatggggatatctatgggatcaaccaggccttaggtgctacagctaaagtcatcaccgaccctgatatcctgaaaacctgtgtaccagacctaagtgacaagagactggaagtggttgggctggagggtgcaattgagatgggccaaatctataccaagctcaagaatgctggacgtcggctggccaagtgctctgagatcaccttccacaccacaaaaacccttcccatgcaaattgacggagaaccctggatgcagacgccctgtacaatcgtagatcacccacaagaaccagatgcccatgctcatgggcccacccccccgctccaccaatttctttggcttcttgagctaatagggggacacccttggcctccaagccagccttgaacccacctccctgtccctggactctactcccgaggctctgtacattgctgccacatactcctgccagcttgggggagtgttccttcaccctcacagtatttattatcctgcaccacctcactgttccccatgcgcacacacatacacacaccccaaaacacatacattgaaagtgcctcatctgaataaaatgacttgtgtttcccctttgggatctgctaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaa (SEQ ID NO: 611) Cblbctgggtcctgtgtgtgccacaggggtggggtgtccagcgagcggtctcctcctcctg NM_170662 NM_aagtgctgctgcggcgtcccgcggcctccccgagtcgggcgggaggggagagc 001033238gggtgtggatttgtcttgacggtaattgttgcgtttccacgtctcggaggcctgcgcgctgggttgctccttcttcgggagcgagctgttacagcgatcccactcccagccggggctccccacacacactgggctgcgtgcgtgtggagtgggacccgcgcacacgcgtgtctaggacagctacggcgccgaaagaactaaaattccagatggcaaactcaatgaatggcagaaaccctggtggtcgaggaggaaatccccgaaaaggtcgaattttgggtattattgatgctattcaggatgcagttggaccccctaagcaagctgccgcagatcgcaggaccgtggagaagacttggaagacatggacaaagtggtaagactgtgccaaaatcccaaacttcagttgaaaaatagcccaccatatatacttgatattttgcctgatacatatcagcatttacgacttatattgagtaaatatgatgacaaccagaaacttgcccaactcagtgagaatgagtactttaaaatctacattgatttgccttatgaaaaagtcaaaacgggcaataagactctttaaagaaggcaaggagagttatgtatgaagaacagtcacaggacagacgaaatctcacaaaactgtcccttatcttcagtcacatgctggcagaaatcaaagcaatctttcccaatggtcaattccagggagataactttcgtatcacaaaagcagatgctgctgaattctggagaaagttttttggagacaaaactatcgtaccatggaaagtattcagacagtgccttcatgaggtccaccagattagctctggcctggaagcaatggctctaaaatcaacaattgatttaacttgcaatgattacatttcagtttttgaatttgatatttttaccaggctgtttcagccttggggctctattttgcggaattggaatttcttagctgtgacacatccaggttacatggcatttctcacatatgatgaagttaaagcacgactacagaaatatagcaccaaacccggaagctatattttccggttaagttgcactcgattgggacagtgggccattggctatgtgactggggatgggaatatcttacagaccatacctcataacaagcccttatttcaagccctgattgatggcagcagggaaggattttatctttatcctgatgggaggagttataatcctgatttaactggattatgtgaacctacacctcatgaccatataaaagttacacaggaacaatatgaattatattgtgaaatgggctccacttttcagctctgtaagatttgtgcagagaatgacaaagatgtcaagattgagccttgtgggcatttgatgtgcacctcttgccttacggcatggcaggagtcggatggtcagggctgccctttctgtcgttgtgaaataaaaggaactgagcccataatcgtggacccctttgatccaagagatgaaggctccaggtgttgcagcatcattgacccctttggcatcccgatgctagacttggacgacgatgatgatcgtgaggagtccttgatgatgaatcggttggcaaacgtccgaaagtgcactgacaggcagaactcaccagtcacatcaccaggatcctctccccttgcccagagaagaaagccacagcctgacccactccagatcccacatctaagcctgccacccgtgcctcctcgcctggatctaattcagaaaggcatagttagatctccctgtggcagcccaacgggttcaccaaagtcttctccttgcatggtgagaaaacaagataaaccactcccagcaccacctcctcccttaagagatcctcctccaccgccacctgaaagacctccaccaatcccaccagacaatagactgagtagacacatccatcatgtggaaagcgtgccttccagagacccgccaatgcctcttgaagcatggtgccctcgggatgtgtttgggttctaatcagcttgtgggatgtcgactcctaggggagggctctccaaaacctggaatcacagcgagttcaaatgtcaatggaaggcacagtagagtgggctctgacccagtgcttatgcggaaacacagacgccatgatttgcctttagaaggagctaaggtcttttccaatggtcaccttggaagtgaagaatatgatgttcctccccggctttctcctcctcctccagttaccaccctcctccctagcataaagtgtactggtccgttagcaaattctctttcagagaaaacaagagacccagtagaggaagatgatgatgaatacaagattccttcatcccaccctgtttccctgaattcacaaccatctcattgtcataatgtaaaacctcctgttcggtcttgtgataatggtcactgtatgctgaatggaacacatggtccatcttcagagaagaaatcaaacatccctgacttaagcatatatttaaagggagatgtttttgattcagcctctgatcccgtgccattaccacctgccaggcctccaactcgggacaatccaaagcatggttcttcactcaacaggacgccctctgattatgatcttctcatccctccattaggtgaagatgcttttgatgccctccctccatctctcccacctccccatcctcctgcaaggcatagtctcattgaacattcaaaacctcctggctccagtagccggccatcctcaggacaggatctttttcttcttccttcagatccctttgttgatctagcaagtggccaagttcctttgcctcctgctagaaggttaccaggtgaaaatgtcaaaactaacagaacatcacaggactatgatcagcttccttcatgttcagatggttcacaggcaccagccagaccccctaaaccacgaccgcgcaggactgcaccagttaattcaccacagattaaccccatgggcctgaggcggcattggaaaatgtcgatgcaaaaattgcaaaactcatgggagagggttatgcctttgaagaggtgaagagagccttagagatagcccagaataatgtcgaagttgcccggagcatcctccgagaatttgccttccctcctccagtatccccacgtctaaatctatagcagccagaactgtagacaccaaaatggaaagcaatcgatgtattccaagagtgtggaaataaagagaactgagatggaattcaagagagaagtgtctcctcctcgtgtagcagcttgagaagaggcttgggagtgcagcttctcaaaggagaccgatgcttgctcaggatgtcgacagctgtggcttccttgtttttgctagccatatttttaaatcagggttgaactgacaaaaataatttaaagacgtttacttcccttgaactttgaacctgtgaaatgctttaccttgtttacagtttggcaaagttgcagtttgttcttgtttttagtttagttttgttttggtgttttgatacctgtactgtgttcttcacagaccctttgtagcgtggtcaggtctgctgtaacatttcccaccaactctcttgctgtccacatcaacagctaaatcatttattcatatggatctctaccatccccatgccttgcccaggtccagttccatttctctcattcacaagatgctttgaaggttctgattttcaactgatcaaactaatgcaaaaaaaaaaaagtatgtattcttcactactgagtttcttctttggaaaccatcactattgagagatgggaaaaacctgaatgtataaagcatttatttgtcaataaactgccttttgtaaggggttttcacataacata (SEQ ID NO: 612) Mdficcccaggccggctctggcctcctgacccagacagcgcagggcgcgagggatcgcg NM_ NM_175088cggccgagcccgggtcgcgccgctcccagcatcggggccgctagccaagagttcg 001166345aggccttcccgatccggatgtgatgaaaaagagcaacagagggagaagtgtttcaggattgtaggagtggaagaggggaaagagaggcagagagggggaaggccccctcgcaggggagccggctggagtgagctggctggaaagagggggcggagtgcgcggagtcagagccgccaccgctgccgcagttgccgccactgcggcgtctgggctgagccggagggaggcgggaggacgcgcaggggcggccgccgccgtcgtcaggccaccggggcgaaaatgcggccgctgccggaggctcgctaactttccggggcggaagaggaggaggaggaggaggaaggggcttggagcgactacggggggatgcggagaagcagtcagttccctgcacccagcacctcacagcccttcctccgtgcgccctgccgggcggcgagctaggcggcagcggcgcggcgcgggctcggcggagcggcccatgtccggcgcgggcgaagccctcgctcccgggcccgtggggccgcagcgcgtggccgaggcgggcggcggccagctgggctccacagcccagggaaaatgtgataaagacaatactgagaaagatataactcaagctaccaatagccacttcacacatggagagatgcaagaccagtccatttggggaaatccttcggatggtgaactcattagaacccaacctcagcgcttgcctcagcttcagacttcagcccaggtgccaagtggtgaggaaataggcaagataaagaacggccacacaggtctgagcaatggaaatggaattcaccacggggccaaacacggatccgcagataatcgcaaactttcagcacctgtttctcaaaaaatgcatagaaaaattcagtccagcagtctgtaaacagcgatatcagtaagaagagcaaagtaaatgctgtcttttcccaaaagacaggctcttcacctgaagattgttgtgtccactgtatcctggcttgcttgttctgcgaattcctgaccctttgcaacattgtcctcggacaaccctcatgtggcatctgcacctcagaagcctgctgctgttgctgtggtgacgagatgggggatgattgtaactgcccttgtgatatggactgtggcatcatggatgcctgttgtgaatcatcagactgcttggaaatctgtatggaatgctgtggaatttgttttccttcataaatatttatcttttgtttgtgttaaaactggagagtgtttaaaaatttccttttggggggaagaaaagcacattgtaagattctcatgaaacaacatggaatttgcactgttaactcattattgtaagtaatctctgaaagcctttttacttaaccaaatctacatggtttaatatgtgaaattttaactactttaactagttttataaatttcttaatatgttacaataacttagggacattttgacaccccccttcccaaatgttaaatgccttctcctttttaccgatatttctgtttcttttaaccgttctcaggagcactttgctccaaatatattatttttcagtgtgtatttaaacgaggcagtttattttgatatgtatctattcatgattgaaaggaagcagtcttggccaggcacggtggcttacacctgtaaccctggcattttgggaggccaaggtgggcagattgcctgagctcaggagttcgagaccagccagggcaacatggtgaaaccccatctctactaaaatacaaaaagttagctgggcttggcggtgtgcgcctgtagtcccagctactcaggaggctgaggcaggagaattgcttgaacccgagaggcggaagttgcagtgagccgagattgtgccactgaactccaacctgcactccagcctgggcaacagagcgagactccatctctaaataaataaatttaataaataaataaataaataaataaataaacaaaccagtctttattttaaaagaaactttaggaaacaaacccacataatagttgggaaccagtgttgatctctctcccttaccttctccacttgttcaacagactctgaatgccgactgtgtggactctcttcctcagactgtggggacagatacaattccactcctgtccacaggaacatgagatttagcagactaaggagatctgtaaagaatgaaccataccacaaggcatactgaagtgaggattataagagaaataaactcaaaatgctgttggaatatgcagagaattgctaccagaatattcagtaaggtttcagggagaatgtggcattttgaggactctcttagaatgagtgattcacctgctatttaaatgaatttttttagatttttgacaaagatttaggtggacaccctaaactgtgtgtgcctttaaccagttaaaagaacagtgccttcagcattcttttttattagttgtaggaatacagctttttgaaaaagctataaagtttaaattaactaaaaatatgcattttcttacacataatttaaatgttatcatacttttttgatgaaaacataatgccttagtaaaatagctctatttaataaagaagattgagtactctgacacatttcatttattattaggaaatttttaatattaaaatcccagtgttctgagttattgaaaggcatcttttattttgagagctttaggtctttttgggatgagaacattttagttgtttagtttgtttcttaagcagtgctattttttgtaaacacagataaatggaaaccattcttttcaatgcagaagaaatctagatatcccctactgtgaccaaatttctgtattacgattttatgttaaattaaactaatatggcaggttataatgatccttaagtgtaaagaaatcagtcaattacaagagtaattgtatagttattgagacctctagtgtgtggcttagatgaaagggagagtaaattttcataccatgctctctcctactcagtttgatctctctaaaattgtagtttggtttgatttaatataattcttagtagaaattttgaaagtatgctttgggattaataattatttttaatttttctggctgaatatcaaattgatagtaacaacagaagcataattttaggaaggctttcgcaaacctagccttttaagagaggtttttaacctgaagcatgagaatatatcacctgtggtttctccatgagatgaaacgtagtttctagttatatcattacttaaagggcttaaaaagaaaaaacttagcaaacttttgaatctttcttttattgctatttacacatacatacacacatacaaacacctttaaattttgggatctgaatataattctggtaaacagctgtcttcatttttctcctctttaagaacttaattcatttgttacataaaatataaggaaatctttatactattttacagtaaccacaatctaaatatttacatatacccaaaattaacttatgctcatatattaggatgtgagaatatcatctgtttatggacacatgaaacctcctaatgacctggaattgttagaatatttgactttttatatgcaaagtttttcaaccaagtggtttgtctaatatttaaacatgtactggcacaatttgtgatgaaaatattagcacatttgcaataatgtttctccataacagagaatgttaatggataccagaattttatttttgtatttatgttcatagtacttttcctcttgtctactccagacagttattccataaagcatttgtataattaaaaggaaaacagaaaaaggaaaagtaggcaaatgtgaaaatagtttcaatatatcttatgatttcttcatgtaaaatgttttgttgaagtatatggctatcatgactaagtgctagaatttatagttacaggcggtgtccttttaaatgtggaaaggcttttaaaatattttaaaactggacctgtattatcctgaatacactatatgaaaatttttaaaaatgacttctttattttgctttaccgtatgtttatatctaattgacatattgactaatgtttgaaagaattcaaccataagttaaaatctgaaggttatctttatcatgtttcatccctgtctgaagatttcctagtcttcttatgtaaatcacatgactcatgtccgtaaatgaactatgaaagattacgatcagtttatgatcattgacatgtgatttcaaaacacagtgttcttttaaaaatctataatatgtcaaaatacaagttttttttttttacatcgttttagtaagttaatttcatttatttactttggagctatatttccacttagaaaaactaaggtaattttacaatatatgctgagattaaaaaccaaggtaaaaatgatcaaacatatatgaaattgagtcttagatttaatgaatacactcgaaaataaatgatcagaagaattttcatctaaggcatagagtggcgaaatttttgtaaatgctcgcagttagcatctaactattaacaatacagtatgactttatttaggagaaggctttttatttagaaaattattttttcatttttacagtgtatcaactgtatccattttcctcacctggatagtcaatgttatctgagcagttcaaggagtaaccaaggcaaccttatgtaataactttccattctttatccatacaaactctttcagtgccctagattctaatgttataaacgtcaaacatcactgcccttacataaataagactcgagacttattttacataaataagtatcttgccttcttgaatgctagttaaatgcttagatttacctaactgcctaatgaatcaggttatttgttaataagattatttttcaaattatttaagacctttatgccccttccaattacttgtgatttgtaggcctgtaggattgttgcatctaatctgactggcaacagaaaatgtcatcaaatactataatatccattttgttttcttttgcactaatacaacagaacatatcatttttgttttaaacaatggttaatatattaatagggtttgttccacacttactatttatagtttttataatcaagcattgggtattaaaagagaatcctttcaacccttcatcttcgtatgcttatacaataaattgcagtgagtgt (SEQ ID NO: 613) Entpd1agggaagaagggagaaagagagagagatttgaatatacattgcttcaaggatgcaa NM_001776NM_009848 aaaattacaacctggaaaaggcttcgagtaactttaggaaaatgagctgctggactcctcagtcaatctgtcctttctagtcaatgaaaaagacagggtttgaggttccttccgaaacggggccggctaatttagcccctcccacgagcccaagggtctgttatatctctgtttccttgaggacctctctcacggagacggaccacagcaagcagaggctgggggggggaaagacgaggaaagaggaggaaaacaaaagctgctacttatggaagatacaaaggagtctaacgtgaagacatttgctccaagaatatcctagccatcctggctctcctctatcatagctgtgatagctttgctgctgtggggttgacccagaacaaagcattgccagaaaacgtaagtatgggatgtgctggatgcgggttcttctcacacaagtttatacatctataagtggccagcagaaaaggagaatgacacaggcgtggtgcatcaagtagaagaatgcagggttaaaggtcctggaatctcaaaattgttcagaaagtaaatgaaataggcatttacctgactgattgcatggaaagagctagggaagtgattccaaggtcccagcaccaagagacacccgtttacctgggagccacggcaggcatgcggttgctcaggatggaaagtgaagagttggcagacagggttctggatgtggtggagaggagcctcagcaacttccccttgacttccagggtgccaggatcattactggccaagaggaaggtgcctatggctggatactatcaactatctgctgggcaaattcagtcagaaaacaaggtggttcagcatagtcccatatgaaaccaataatcaggaaacctttggagcttggaccttgggggagcctctacacaagtcacttttgtaccccaaaaccagactatcgagtccccagataatgctctgcaattcgcctctatggcaaggactacaatgtctacacacatagctcttgtgctatgggaaggatcaggcactctggcagaaactggccaaggacattcaggttgcaagtaatgaaattctcagggacccatgctttcatcctggatataagaaggtagtgaacgtaagtgacctttacaagaccccctgcaccaagagatttgagatgactcttccattccagcagtttgaaatccagggtattggaaactatcaacaatgccatcaaagcatcctggagctcttcaacaccagttactgcccttactcccagtgtgccttcaatgggattttcttgccaccactccagggggattttggggcattttcagctttttactttgtgatgaagtttttaaacttgacatcgagaaagtctctcaggaaaaggtgactgagatgatgaaaaagttctgtgctcagccttgggaggagataaaaacatcttacgctggagtaaaggagaagtacctgagtgaatactgcttttctggtacctacattctctccctccttctgcaaggctatcatttcacagctgattcctgggagcacatccatttcattggcaagatccagggcagcgacgccggctggactttgggctacatgctgaacctgaccaacatgatcccagctgagcaaccattgtccacacctctctcccactccacctatgtcttcctcatggttctattctccctggtccttttcacagtggccatcataggcttgcttatctttcacaagccttcatatttctggaaagatatggtatagcaaaagcagctgaaatatgctggctggagtgaggaaaaaaatcgtccagggagcattttcctccatcgcagtgttcaaggccatccttccctgtctgccagggccagtcttgacgagtgtgaagcttccttggcttttactgaagcctttcttttggaggtattcaatatcctttgcctcaaggacttcggcagatactgtctctttcatgagtttttcccagctacacctttctcctttgtactttgtgcttgtataggttttaaagacctgacacctttcataatctttgctttataaaagaacaatattgactttgtctagaagaactgagagtcttgagtcctgtgataggaggctgagctggctgaaagaagaatctcaggaactggttcagttgtactctttaagaacccctttctctctcctgtttgccatccattaagaaagccatatgatgcctttggagaaggcagacacacattccattcccagcctgctctgtgggtaggagaattttctacagtaggcaaatatgtgctaaagccaaagagttttataaggaaatatatgtgctcatgcagtcaatacagttctcaatcccacccaaagcaggtatgtcaataaatcacatattcctaggtgatacccaaatgctacagagtggaacactcagacctgagatttgcaaaaagcagatgtaaatatatgcattcaaacatcagggcttactatgaggtaggtggtatatacatgtcacaaataaaaatacagttacaactcagggtcactaataatgcatcttccaatgcatatttttattatggtaaaatatacataaatataattcaccattttaacatttaattcatattaaatacgtacaaatcagtgacatttagtacattcacagtgttgtgccaccatcaccactatttagttccagaacatttgcatcatcaatacattgtctagagacaagactatcctgggtaggcagaaaccatagatcttttgtgtttacagctatggaaaccaactgtaccataaagatagttcactgagttttaaagccaagccacatcttatttttccaaggtttaatttagtgagagggcagcattagtgtggagtggcatgcttttgccctatcgtggaatttacacatcagaatgtgcaggatccaagtctgaaagtgttgccacccgtcacacaacatgggctttgtttgcttattccatgaagcagcagctatagaccttaccatggaaacatgaagagaccctgcacccctttccttaaggattgctgcaagagttacctgttgagcaggattgactggtgatgtttcattctgaccttgtcccaagctctccatctctagatctggggactgactgttgagctgatggggaaagaaaagctctcacacaaaccggaagccaaatgtcccctatctcttgaatgatcaagtcacttttgacaacatccaggtgaatataaaaacttaataaagctgtggaaaggaactcttaatcttcttttctgctacttaggttaaattcactttgatcttgattaggaatcaaaattcgaattgggacatgttcaaattctttcttgtggtagttgcctatactgtcatcgctgctgttggttgagcatttgtggtgtaccacgctgtgtgctcaagggtattacattctttcttctcatttaatcctcacaacaatctgaagaaggtaggtattacaattcccacttcatagaaacagaaactgaggttcagagaggttaagtcatttgcccaaatggctgagccaaagcctaccatgtacctaacctttattttctttcccgaacataccaggctgtctcctcataacttccaagcatgcacttaaaactccacatgaatacaaggttcatgggacttggtattcatagaaagggaggcagaaagctggtctgttcctgataggcttgtaatttaattttcattctgttcatgtgctttggatggaagcacatctggcatatgatgctaatcagtggttcccatacccctggcttcctaattttaatgtttgctcacagcatagtagattgacatcaaatagtggccgatgatgatgaaaataaaggtcaaataagttgagccaataacagccgcttttttccttctgtctgcgtatacaaagcactgtcatgcacacaatctattctgaccctcacaacaacccataagggtgtaaatagtatttccattttacaaatgaggatcacacaaactactacatggcagagcagatactccaactcatgtcttctggttgaagcctattgctttttcttttctaaacactttccctcagcaagttggaattagacttcacaagtctccttcagagaacacaaatcttttcttattccattcctgtttggttgcctacgtccaatctccccctccccagagatgccaaaaaaaaaatcctttaaggtatttgggagccaaactcaacttgttaaaatctcaaattatggagacaatcagcagacacaacctaaccccaattattttggcaggaaggttggtttagaggcagatccagcaatctgctttgggccactctgggtggggtaggtgaaataagattggtcactgttaactaattttaatattggattggccattggttatcactgattaccattctcccctggattttcacccaggactcaaaacttggttctgctaaccctgttcctttatgaggaaccttttaaagattcctttataaggtgggagttttttttctatgaacctataggggagaaaaaagatcagcagaagtcattacttttttttttttttttttttttttttgagagagagtctcactccattgcccaggctggagtgcagtggtgctatctcggctcactgcaacctccgcctcctgggttcaagcaattctcctgcctcagcctcccgagtagctgggattgcaggtgcccaccaccacacccggctaatttttgtatttttagtaaagacagggtttcaccatgttggccaggctggtctccaactcccaatctcaggtgatcctattgcctcgggctcccaaagtgctgggattacaggagtgagccaccatgcctggccagaagtggttacttctgtagacaaaagaataatgctacttaatcaggctttctgtgtgacaagaaagagaaagaaaataaagaagtttcaattcatccaattcttaataagaaatatgtaaataaaattttttaaaattacacttcattttaatgttgtatcagtcaaggtccctgcaagagatggatggtatggtacactcaaactgggtaacacaggagagttttcagaaagcaactaaatccaaaatactatcaaggaatcaatataaaaattgttaatatttttctcatactaaattttcaaaatattttgtgtctattacatttacagcacatcttaattaggactagctgtgtgttcacctcacatgtggcttgtagctaccatactggacagcacatgtccaaaaaaatacacgtaaagttaaagtttaaaagacacaggaactaagccctcattgtctttcccttgggaggtagtttaaagagctatagatgctgtaacattcttgctattatttattatatatgacattattcctaaaaaagcttttgagatcctaggttgtattcctcaggttttgttgccttcccatgaagatgtgaaggcagggatgcctgttattcagtccaagatgcatgacaagagacatgggaaagtttcatctggatttaaagattaattcttgatgcttacattccatactcaaaatgtaaatttgaatattaaaataaagatgattttttttttggagctagtcttgctctgttgcccaggctggaatgcagtggcatgatcatggctcactgcagcctcgacctcccaagctcaagcaaggctacaggtgtgcacctaagtagctaggactacaggtgtgcaccaccatgtctagctatttttttttctgtagagacagggttttcctatgttgtccaggctggtctcgaactcctgccctcaagcaatcctcctgccttggcctcccaaagtgttgagattacaggcgtaagccactgcacctggccaagatgaatattttaatagctcacagaacaaagtttgccacataatgataaaattactatgaaaatatattccctttattgtcagtttaaaagatgaactgagtttcacccaaactggtctggcccctctctgattcaaataccaatagttgctctgattcaattttccaactgttagaacatgacagctgctcataactagctttgcttactaaccatgtttctttccatttgtattaggtcctttactttttataacagcctcaaagtttcatgaattgctgcagtaaacattgattttcatgtttgtgagtctgcaagccagctgggcagctctacttcaggtggtaagggtggatcagacctattccatatacctcttgttctccttgtccagtggtttctagggatatgttctcatgatgaaccccgcagaggctcgtgaaagtgagaggaaactaggatgcctcttaaggtcttggtcaggatggggtctcctgtcacttctgtcacaggctattgtaagtcatatgagcaagctcaataaaatataaacaagtcagataaacagtgggaggaatggcaaagtcatatggccaaggccatgagtgattaattttaacacaggaaaaaagtttaagcattaaatgcgattatttaatatacaatgtcttattaactgaaatataaaatgtgtttactgtaaaatataatctgtttatctcaccaaagaaatattatctttaaaaaatgtcattacttctaagacatcatcagtctgcaacttctttccatttgccttaatcaggatgctgtggcagctcccacattagcctcgcattctaaactggtagatgtcctaggaaaccatacatctatgtatttttcttattttatacgtttaggacaatgtatagctaattacccaactttttatttgcatacaaatctaatacaactgaacacaatcagttttatcacaggtataatggatttttcaatagtgaggaggtgcctccatgagccttctctttagaaaagtggcattcaagactcttcatttgaagtgaagattgctatgtcttttgcattgctctattttacataaattaagttataaattgacactataatcaaagacaccatgatcagtgatgtttgatcaccctcatcagcactagagttgacttgtttttataacccctttgcatgtatgttgaatagcaaagttcatcagagaacatgtattagtcaatggtaagtaagatactctcatctaagaaataacatcacctcttctaatgaagttctaagaagagagggaagaaaaagtcttgggagctagtcagggaatagtgtgtatttgcaattacctaaactgaactctaccattttctcctaacccagttcctcctcctgtgttttttcatgattaatgccacccctgcctcaatgaaccaagatcagctccatcactgggacctccccattctgcctgtgcaatatttttcttttttatttctccttctaatattactgttattgctccagtaaagagctgtaatatattttacctggactgataccaggaatggtggtgttgcttccaatctgttgctgctagattaatctttgcaaagcacaggcttaatttcattgctgctcaactaaaaccactggtggctttccattgcctacaaaataaagtcaacctocccatcagacattcaaggctttcaatgatccatggccgccagctctttccaggctcatatcccactccactcctctgatgtttcctacactacactacactatactacactacagccaggtagaatgactgttcacccaacaccactcaggttgtcttctcaacttggaatactcttgcaccttcaaagctcatttcaaatgccccttcatttgtgaagccttctccaaatttccaagtcagaatgtctcttccttgtgctaccacaaccctttaactgagcctccattagtgcactgagaccattctgttcagtgtctgggtgaagcttcctggtgaaaaatatgttacctatttctttctgaaaagttggattcagggatattatcacggacctaaggtaatagttctagccaacctccctgtccactgccaggccgactacaaacccttctgttgctggcgagctggtccgcaccactagttctgcttcactctatttatctcttgatgtaaccatcttctttctccaggttttaagaaccagcccaactcctggttccctgatgaagcttttattcccctagccacatggaacttttcctttttggaacatgcctttagtttctgtgtagtttgccatgcagcacttcattgtacacattattaaaacagaattttaaggattagaatgaaccttaaaagatcatgcatctcaaaatttaatgtacatacaaattacccagggattttgttgaaataaaaattatttaattttaattaatataaataattcagtaggtctggggtgaggcctgaggttttacatttccaacaagctgccaggtaaagccaatacatctgtccaggaatcacactttgcgtatcaaaggtctagatgacattatcattccaaagagtttcttttacaggctctcagatcagtgttcatccactacctgactactgtcattcacaggcattctgttccacagcaggccagctaacgtggtatttacaaagctcactcctcttatacaacaatccaagtgtttcttttgtcagttgtctgtgccccaggagatccctctctgccttgccttgccctctgcctttggagaccagcacctcatactcagtgaaggcctggagtgcttaagagggatttcttccagctctcttgccctggtcttcagtgtattagatgtattacctccatgctctcagtagaggcccataggaaagagtaggtaggttatgccagctcacacgcatcctttaaaaatggtttagaagtttagctggtttcttattactcctgtctatggatgtttccttctgtcactctactagggatgaaacagctaatcatgttcaatagttacatttagattggtttttaaaaactatgattgtattagttcgtttccatgctgctgataaagacatatctgagactggaaacaaaaagggtttaattggacttacagttccacatggctggggaggcctcaaaatcaggtgggaggcaaaaggtacttcttacgtggtggcatcaagagcaaaatgaggaagaagcaaaagcagaaactcttcataaacccaccagatcttgtgggacttattatcacgagaatagcacagaaaagactggcctccatgattcaattacctcccactgcgtccctcccacaacatgtgggaattctgggagatacaattcaagttgagatttgggtggggacacagccaaaccatatcattcctccctgggctcctccaaatttcataatcctcacatttcaaaaccaatcattccttcccaacagttccccaaagtcttaactcaattcagcattaacccaaaagtccacagtccaaagtctcatctgagacaaggcaagtcccttccacttacaagcctgtaaaagcaagctagttacctcctagatacaatggggggtacaggtattgggtaaatacagctgttccaaatgagagaaattggccaaaacaaaggggttacagggtccatgcaagtctgaaatccagtggggcagtcaaattttaaagctccataatgatctcctttgactccatgtctcacattcaggtcatgctgatgcaagagataggttcccatggtcttgtgcagctccgcccctgtggctttgcagagtacagcctccctcctggctgctttctcaggctgatgttgagtgtctgtagcttttccaggcacaagatgcaagttggtggttgatctaccattctggggtcaccattctggggtctaccgttctgggactgtggccttcttctcacagctccactaggcagtgccccaacagggactctgtgtgggggctctgccccacatttcccttccacactgccctaggagaggttccccatgagggctctgcccctgcagcaaacttttgcctggacatccaggtgtttccatatatattctgaaatctaggcagaggttcccaaatctcaattcttgacatctctgcacccacaggctcaacatcacatggaagctgccaatgcttggggcctctaccctctgaagccacagcccaagctctatgttggctcctttcagccatggctggagcagctgggacacagggcaccaagtccctaggctgcacacagcacagagaccctgggcccagcccacaaaaccactttttcctcctgggcctctgggcctgtgatgggaggggctgccatgaaggtctctgacatgacctggagacattttccccatggtcaggggattaacattaggctccttgctgcttatgcaaatttagcagccagcttgaatttctccttaaaaaaaatgggtttttcttttctactgcatcatcaggctgcagattttccacatttatgctcttgtttcccttttaaaacagaatgtttttaacagcacccaagtcaccttttgaatgctttgctgcttagaaatttattccaccagataccctaagtcatctctctcaagctctaagttccacaaatctctagggcaagggtgaaatgctgccagtctccttgctaaaacataacaagggtcacctttacttcagttcccaacaaggtcttcatctccatctgagaccacctcagcctggaccttattgttcatatcactatcagtatttttgtcaatgccattcacagtctctaggaggttccaaactttcctacattttcctatcttcttctgagccctccagattatttcaacacccagttccaaagttgcttccacattttcgggtatcttttcagcaatgccccactctactggtactattagtccattttcatgctgctgataaagacatacctgagactgggaacaaaaagaggtttaattggacttatagttccacctggctggggaggcctcagaatcatggcaggaggtgaaaggcatttcttacacggcagcagcaagagaaaaatgaagaagcagcaaaagcagaaacccctgataaaaccatcagatctcgtgagacttattcactatcacaagaatagcatgggaaagaccagcccccttgattcaattacctccccctgggtcctgtgggaattctggaaggtacaattcaatttgagatttgggtggggacacagccaaaccatatcaatgattttgtactttaaccagctgaatggaagtacaatctcttgctatatgacacaataattatttgcaaaatgagtaaacatatcataaggaaattatttttacaaggtttgaaacctgaaatgcagtctattatcatacataactaaaaatagagcctcaataaacagattcccagttttgaaaatgcaacatttgtactccacattgtcagttttcttaggtatatttataaatactcctataaaaatgtaaagaaacacataatgtagattgctaattttataataacacaagttgattttgacatccaacttattaattatgaaatgacttttggcctagtaacaatgaaaatgggggcaaatacagataaatggtaattcttagaatgaactactcagcaccaattctaagtttttcttgatggtaaatcataatgttccctttctcctcggttctgcaatctataggcatcccataattgtaatcaatagcttaaaaatatgtctctctgtcctattctgtatctgtatctcttggatttttacctttgcaatagtcaactgaaccatcttcttggagtactcatgaagatggaagtctacatggagaatacaggatgaatccactctgtctcctgcagtgaagtctgtttgaaggatgtatttggctgtcttctggacaggccattctaataacagaaacaaacaagttattttaaaacttattggaatattcaaatattaaccaaagtagaaaaatataatacacatccatgtgcccatcacagaacttcactgattatcatcatttagccagtcttgaagaagcaagtgctaattacaatcacaaatgaaacaagattcagacttcatgaagagcactgcgctataataaaagaagaaatgagcacatacattcttttactgacagtcaaatggtgaaggtgggcagaatcattatgtgatgcaacatggcaaaagtatacagacagtgcatccagaggaaggcaccttgctgaatgactagaatggaagtaggagacattttgcaggcccccttcatcctgcagggagaaccagaaccacagcagctctatttgcctattcctctttaaattacaaagttaaaatttgggagtagtagaaaatcaattggttatcttatagagtctcctagaatatttcattggcattgagaaggtggaaaatgcaaattatatactttaaaatgtaaatttgcttttcacatatgcttaaagcctaaaacctcttaataaacttcttctgaaatata (SEQ ID NO: 614) Dgkzggagagtgtctctaaggtgacactcgggtgcgcggcagcagcggcggttgcagga NM_201532NM_13806 ggagagtgtctctaaggtgacactcgggtgcgcggcagcagcggcggttgcaggagctcgctctccgcccgggctccggctccgctccagccgtccggggggcgccgcggcgcgcagagcgcagcaccccgactccagccaggagcccccgcccccccggagcgcaggaggaccccggcccgcctctcccaggcgcagcgcccagcatctcgctgctcctgtcgtctaagcgtcggcgtcgctagggacctgcggatcccggcgctcccctccctccccgcctcgcgtccccggcccgggcggactggagactcgaacttgagcgggtgcccgaaaggccgcaggagccgcgggcggaaggcggccgcacgatggccgaggggcagggcggcggagggcagcgctgggactgggctggcggcggccgggcagccgaggaggaggtggtgcggcggcgtttgccggcgcggggaggaggcccaggtcgcgcagccctggcccgagggttcccggggcacggccgctgggcccccggtggaggagcgtttccgccagctgcacctacgaaagcaggtgtcttacaggaaagccatcaccaagtcgggcctccagcacctggccccccctccgcccacccctggggccccgtgcagcgagtcagagcggcagatccggagtacagtggactggagcgagtcagcgacatatggggagcacatctggttcgagaccaacgtgtccggggacttctgctacgttggggagcagtactgtgtagccaggatgctgaagtcagtgtttcgaagaaagtgcgcagcctgcaagattgtggtgcacacgccctgcatcgagcagctggagaagataaatttccgctgtaagccgtccttccgtgaatcaggctccaggaatgtccgcgagccaacctttgtacggcaccactgggtacacagacgacgccaggacggcaagtgtcggcactgtgggaagggattccagcagaagttcaccttccacagcaaggagattgtggccatcagctgctcgtggtgcaagcaggcataccacagcaaggtgtcctgcttcatgctgcagcagatcgaggagccgtgctcgctgggggtccacgcagccgtggtcatcccgcccacctggatcctccgcgcccggaggccccagaatactctgaaagcaagcaagaagaagaagagggctttccttcaagaggtagtccagcaagaaagggcctgaggagggccgctggagacccttcatcatcaggcccaccccctccccgctcatgaagcccctgctggtgtttgtgaaccccaagagtgggggcaaccagggtgcaaagatcattccagtctttcctctggtatctcaatccccgacaagtcttcgacctgagccagggagggcccaaggaggcgctggagatgtaccgcaaagtgcacaacctgcggatcctggcgtgcgggggcgacggcacggtgggctggatcctctccaccctggaccagctacgcctgaagccgccaccccctgttgccatcctgcccctgggtactggcaacgacttggcccgaaccctcaactggggtgggggctacacagatgagcctgtgtccaagatcctctcccacgtggaggaggggaacgtggtacagctggaccgctgggacctccacgctgagcccaaccccgaggcagggcctgaggaccgagatgaaggcgccaccgaccggttgcccctggatgtcttcaacaactacttcagcctgggctttgacgcccacgtcaccctggagttccacgagtctcgagaggccaacccagagaaattcaacagccgctttcggaataagatgttctacgccgggacagctttctctgacttcctgatgggcagctccaaggacctggccaagcacatccgagtggtgtgtgatggaatggacttgactcccaagatccaggacagaaaccccagtgtgttgttttcctgaacatccccaggtcctgtgcgggcaccatgccctggggccaccctggggagcaccacgactttgagccccagcggcatgacgacggctacctcgaggtcattggcttcaccatgacgtcgttggccgcgctgcaggtgggcggacacggcgagcggctgacgcagtgtcgcgaggtggtgctcaccacatccaaggccatcccggtgcaggtggatggcgagccctgcaagcttgcagcctcacgcatccgcatcgccctgcgcaaccaggccaccatggtgcagaaggccaagcggcggagcgccgcccccctgcacagcgaccagcagccggtgccagagcagttgcgcatccaggtgagtcgcgtcagcatgcacgactatgaggccctgcactacgacaaggagcagctcaaggaggcctctgtgccgctgggcactgtggtggtcccaggagacagtgacctagagctctgccgtgcccacattgagagactccagcaggagcccgatggtgctggagccaagtccccgacatgccagaaactgtcccccaagtggtgcttcctggacgccaccactgccagccgcttctacaggatcgaccgagcccaggagcacctcaactatgtgactgagatcgcacaggatgagatttatatcctggaccctgagctgctgggggcatcggcccggcctgacctcccaacccccacttcccctctccccacctcaccctgctcacccacgccccggtcactgcaaggggatgctgcaccccctcaaggtgaagagctgattgaggctgccaagaggaacgacttctgtaagctccaggagctgcaccgagctgggggcgacctcatgcaccgagacgagcagagtcgcacgctcctgcaccacgcagtcagcactggcagcaaggatgtggtccgctacctgctggaccacgcccccccagagatccttgatgcggtggaggaaaacggggagacctgtttgcaccaagcagcggccctgggccagcgcaccatctgccactacatcgtggaggccggggcctcgctcatgaagacagaccagcagggcgacactccccggcagcgggctgagaaggctcaggacaccgagctggccgcctacctggagaaccggcagcactaccagatgatccagcgggaggaccaggagacggctctgtagcgggccgcccacggatcagcaggattggacaatgcggccaggggacgagcgccttccttgcccacctcactgccacattccagtgggacggccacggggggacctaggccccagggaaagagccccatgccgccccctaaggagccgcccagacctagggctggactcaggagctgggggggcctcacctgttcccctgaggaccccgccggacccggaggctcacagggaacaagacacggctgggttggatatgcctttgccggggttctggggcagggcgctccctggccgcagcagatgccctcccaggagtggaggggctggagagggggaggccttcgggaagaggcttcctgggccccctggtcttcggccgggtccccagcccccgctcctgccccaccccacctcctccgggcttcctcccggaaactcagcgcctgctgcacttgcctgccctgctttgcttggcacccgctccggcgaccctccccgctcccctgtcatttcatcgcggactgtgcggcctgggggtggggggcgggactctcacggtgacatgtttacagctgggtgtgactcagtaaagtggatttttttttctttaaaaaaaa (SEQ ID NO: 615) Vamp7attggaggagcgctcccactcccaagaggccacgcgtagacggggcgcttcatgc NM_005638NM_011515 attggaggagcgctcccactcccaagaggccacgcgtagacggggcgcttcatgcggaagtcagcggcgtccggtcccagcctcctctgggagcgggcagttggcgaccctgcactgacccgcgtccctccgtcccgagcccgcgcgccctcagagggtgcccggacagactgaagccatggcgattctttttgctgttgttgccagggggaccactatccttgccaaacatgcttggtgtggaggaaacttcctggaggtgacagagcagattctggctaagataccttctgaaaataacaaactaacgtactcacatggcaattatttgtttcattacatctgccaagacaggattgtatatctttgtatcactgatgatgattttgaacgttcccgagcctttaattttctgaatgagagaaagaagagcttccagactacttacggttcaagagcacagacagcacttccatatgccatgaatagcgagttctcaagtgtcttagctgcacagctgaagcatcactctgagaataagggcctagacaaagtgatggagactcaagcccaagtggatgaactgaaaggaatcatggtcagaaacatagatctggtagctcagcgaggagaaagattggaattattgattgacaaaacagaaaatcttgtggattcttctgtcaccttcaaaactaccagcagaaatcttgctcgagccatgtgtatgaagaacctcaagctcactattatcatcatcatcgtatcaattgtgttcatctatatcattgtttcacctctctgtggtggatttacatggccaagctgtgtgaagaaataggaaagaagaagttaccattaaccaaggatatgagagaacaaggagttaaaagcaatccatgtgactcaagcctttcacatactgacagatggtatctgccagtctcttcaaccctcttctcactttttaatatcttgttccatgcctccaggtttatctttgtcttatctaccagtttattcctgtgaacttcagattgaaccattcattgcagcagtagccttaaaaaggcttttgtttatttctttggtttgttaactagtgtcatctatttagagaaacatttttgtttttaattgctcaaagctgtcgccgctagtcttatgagctatctactaaaactatggagaaactttgtatgtgcacacaaaagtattcaagagacagtattgctaacatctcatcttaatgtcttttgttattgagaagttttaggtgcttcaaaacaatataaatggataatagttgttatttggggaattgtaatgatgttggtgctgcttccttctaagagctcagacaagtaaagtatgaaacattcttatttcagttagatggggaacattttgctagcccattagaagcacacagaattatccttgtcctcctaatattgactttcaggaataaagttcagtgtgctgatcattcacaatacagtggatagcttgatatcttctgttttcccattgcagttgatttgagaagatgaaggtttaaatattgttgaaagttgcagttttttaaatgtgttcctttttcttctgtgaatatttagggcaatcgtgtcgctaatagaatatgtagtagagggggtggggaggtaaattcctctgacttgccaaagaaaaagaagggaaccacagtggatatgctagcattttagctgtgcaaagggaggtagtgtgggaaaagtgtttccattctgggaaaagcccaaaccgaatacggtcagcagtcaactccagggtttgggcttgattcctgttgaataatagttttgagcattctttgtggttaaataaattcttaaatctgcctagttttgatgaattcttttgtgaaacttgaaagagaatagacagtatgacatatagaattaatacaaaacagtttaacaaccatttaactgcagtgtaagaattattggactgtaatcatatcgctactggcatctgttatctagttttgcatttctggtgtgtatctgaaaggaagacattttctaccctagatccaattgcatttatttatcaataagtgccattaaattgaaattatattacattttacaattctcaatgaatgaacaaattagtctgtagaatctagccacctgtttagcctagtcatgtgccttgaacatatatgtgtcccatttatctggctcatggtacctgttcttctatccaaacctttcaattcatgctacctgattcatttatttgacatagatcttaggcccacttgaactcttttcttgtttatctagcatagcacaaacgtttttccagtcttctttatcaacactaatgcctcttaattgcatcagtatttcctattggaaaatacatctgttccagaaaaacatttggcattcctgaataatttccaaatgtttttaatccaaagaaaaaggtttaaagcttatttccctttcttatacacacctgaatttaaattgatgtgcatgttttagggatcaattacctaactgttccttggtctatttatgtataagaatgctttttaaagcacatgtctcattttaaatgacgcacaaactgaagatgtaataaaatttaagagtaatacaataaaaaaa (SEQ ID NO: 616)Hipk1 gcagagtctgcagtgcggagggggccgggaagtccaggccccgcactcgatccac NM_198268MM_010432 gctggctccctacggaggcccacctactcgaggcccaccgactcctactgcaatcagtactatgcgatcgtcctagagagtccattcagctgcacttccgcctcagtatggcatcacagctgcaagtgttttcgcccccatcagtgtcgtcgagtgccttctgcagtgcgaagaaactgttaaatagagccctctggctgggatgtttcaggacagagtagcaacgacaaatatttttacccacagcaaaaccctcccagccacacaagggcaagccaactcctctcaccaggtagcaaatttcaacatccctgcttacgaccagggcctcctcctcccagacctgcagtggagcatattgttgtaacagccgctgatagctcgggcagtgctgctacatcaaccttccaaagcagccagaccctgactcacagaagcaacgtttctttgcttgagccatatcaaaaatgtggattgaaacgaaaaagtgaggaagttgacagcaacggtagtgtgcagatcatagaagaacatccccctctcatgctgcaaaacaggactgtggtgggtgctgctgccacaaccaccactgtgaccacaaagagtagcagttccagcggagaaggggattaccagctggtccagcatgagatcctttgctctatgaccaatagctatgaagtcttggagttcctaggccgggggacatttggacaggtggctaagtgctggaagaggagcaccaaggaaattgtggctattaaaatcttgaagaaccacccctcctatgccagacaaggacagattgaagtgagcatcctttcccgcctaagcagtgaaaatgctgatgagtataattttgtccgttcatacgagtgctttcagcataagaatcacacctgccttgtttttgaaatgttggagcagaacttatatgattttctaaagcaaaacaaatttagcccactgccactcaagtacatcagaccaatcttgcagcaggtggccacagccttgatgaagctcatagagtcttggtctgatccacgctgaccttaagcctgaaaacatcatgctggttgatccagttcgccagccctaccgagtgaaggtcattgactttggttctgctagtcacgtttccaaagctgtgtgctcaacctacttacagtcacgttactacagagctcctgaaattattcttgggttaccattttgtgaagctattgatatgtggtcactgggctgtgtgatagctgagctgttcctgggatggcctctttatcctggtgcttcagaatatgatcagattcgttatatttcacaaacacaaggcttgccagctgaatatcttctcagtgccggaacaaaaacaaccaggtttttcaacagagatcctaatttggggtacccactgtggaggcttaagacacctgaagaacatgaactggagactggaataaaatcaaaagaagctcggaagtacatttaaattgcttagatgacatggctcaggtcaatatgtctacagacctggagggaacagacatgttggcagagaaggcagaccgaagagaatacattgatctgttaaagaaaatgctcacaattgatgcagataagagaattacccctctaaaaactcttaaccatcagtttgtgacaatgactcaccttttggattttccacatagcaatcatgttaagtcttgttttcagaacatggagatctgcaagcggagggttcacatgtatgatacagtgagtcagatcaagagtcccttcactacacatgttgccccaaatacaagcacaaatctaaccatgagcttcagcaatcagctcaatacagtgcacaatcaggccagtgttctagcttccagttctactgcagcagctgctactctttctctggctaattcagatgtctcactactaaactaccagtcagctttgtacccatcatctgctgcaccagttcctggagttgcccagcagggtgtttccttgcagcctggaaccacccagatttgcactcagacagatccattccaacagacatttatagtatgtccacctgcgtttcaaactggactacaagcaacaacaaagcattctggattccctgtgaggatggataatgctgtaccgattgtaccccaggcaccagctgctcagccactacagattcagtcaggagttctcacgcagggaagctgtacaccactaatggtagcaactctccaccctcaagtagccaccatcacaccgcagtatgcggtgccctttactctgagctgcgcagccggccggccggcgctggttgaacagactgccgctgtactgcaggcgtggcctggagggactcagcaaattctcctgccttcaacttggcaacagttgcctggggtagctctacacaactctgtccagcccacagcttatgattccagaggccatggggagtggacagcagctagctgactggaggaatgcccactctcatggcaaccagtacagatcttttcatgcagcagccatccttgctgactaaccatgtgacattggccactgctcagcctctgaatgttggtgttgcccatgttgtcagacaacaacaatccagttccctcccttcgaagaagaataagcagtcagctccagtctcttccaagtcctctctagatgttctgccttcccaagtctattctctggttgggagcagtcccctccgcaccacatcttcttataattccttggtccctgtccaagatcagcatcagcccatcatcattccagatactcccagccctcctgtgagtgtcatcactatccgaagtgacactgatgaggaagaggacaacaaatacaagcccagtagctctggactgaagccaaggtctaatgtcatcagttatgtcactgtcaatgattctccagactctgactcttctttgagcagcccttattccactgataccctgagtgctctccgcacccgcactatcattgtgcctccactgaaaactcagcttggtgactgcactgtagcaacccaggcctcaggtctcctgagcaataagactaagccagtcgcttcagtgagtgggcagtcatctggatgctgtatcacccccacagggtatcgagctcaacgcggggggaccagtgcagcacaaccactcaatcttagccagaaccagcagtcatcggcggctccaacctcacaggttgagaagcagcaacccagccccccgcaggcagcaggcgtttgtggcccctctctcccaagccccctacaccttccagcatggcagcccgctacactcgacagggcacccacaccttgccccggcccctgctcacctgccaagccaggctcatctgtatacgtatgctgccccgacttctgctgctgcactgggctcaaccagctccattgctcatcttttctccccacagggttcctcaaggcatgctgcagcctataccactcaccctagcactttggtgcaccaggtccctgtcagtgttgggcccagcctcctcacttctgccagcgtggcccctgctcagtaccaacaccagtttgccacccaatcctacattgggtcttcccgaggctcaacaatttacactggatacccgctgagtcctaccaagatcagccagtattcctacttatagttggtgagcatgagggaggaggaatcatggctaccttctcctggccctgcgttcttaatattgggctatggagagatcctcctttaccctcttgaaatttcttagccagcaacttgttctgcaggggcccactgaagcagaaggtttttctctgggggaacctgtctcagtgttgactgcattgttgtagtcttcccaaagtttgccctatttttaaattcattatttttgtgacagtaattttggtacttggaagagttcagatgcccatcttctgcagttaccaaggaagagagattgttctgaagttaccctctgaaaaatattttgtctctctgacttgatttctataaatgcttttaaaaacaagtgaagcccctctttatttcattttgtgttattgtgattgctggtcaggaaaaatgctgatagaaggagttgaaatctgatgacaaaaaaagaaaaattactttttgtttgtttataaactcagacttgcctattttattttaaaagcggcttacacaatctcccttttgtttattggacatttaaacttacagagtttcagttttgttttaatgtcatattatacttaatgggcaattgttatttttgcaaaactggttacgtattactctgtgttactattgagattctctcaattgctcctgtgtttgttataaagtagtgtttaaaaggcagctcaccatttgctggtaacttaatgtgagagaatccatatctgcgtgaaaacaccaagtattctttttaaatgaagcaccatgaattcttttttaaattattttttaaaagtctttctctctctgattcagcttaaatttttttatcgaaaaagccattaaggtggttattattacatggtggtggtggttttattatttgcaaaatctctgtctattatgagatactggcattgatgagctttgcctaaagattagtatgaattttcagtaatacacctctgttttgctcatctctcccttctgttttatgtgatttgtttggggagaaagctaaaaaaacctgaaaccagataagaacatttcttgtgtatagcttttatacttcaaagtagcttcctttgtatgccagcagcaaattgaatgctctcttattaagacttatataataagtgcatgtaggaattgcaaaaaatattttaaaaatttattactgaatttaaaaatattttagaagttttgtaatggtggtgttttaatattttacataattaaatatgtacatattgattagaaaaatataacaagcaatttttcctgctaacccaaaatgttatttgtaatcaaatgtgtagtgattacacttgaattgtgtacttagtgtgtatgtgatcctccagtgttatcccggagatggattgatgtctccattgtatttaaaccaaaatgaactgatacttgttggaatgtatgtgaactaattgcaattatattagagcatattactgtagtgctgaatgagcaggggatttgcctgcaaggagaggagttcccttggaattgttttgcacaggtgtgtctggtgaggagtttttcagtgtgtgtctcttccttccctttatcctccttcccttattgtagtgccttatatgataatgtagtggttaatagagtttacagtgagcttgccttaggatggaccagcaagcccccgtggaccctttagttgttcaccgggatttatcagaacaggattagcagctgtattgtgtaatgcattgttctcagtttccctgccaacattgaaaaataaaaacagcagcttttctcctttaccaccacctctacccctttccattttggattctcggctgagttctcacagaagcattttccccatgtggctctctcactgtgcgttgctaccttgcttctgtgagaattcaggaagcaggtgagaggagtcaagccaatattaaatatgcattcttttaaagtatgtgcaatcacttttttgaatgaatttttttttccttttcccatgtggcagtccttcctgcacatagttgacattcctagtaaaatatttgcttgttgaaaaaaacatgttaacagatgtgtttataccaaagagcctgttgtattgcttaccatgtccccatactatgaggagaagttttgtggtgccgctggtgacaaggaactcacagaaaggtttcttagctggtgaagaatatagagaaggaaccaaagcctgttgagtcattgaggcttttgaggtttcttttttaacagcttgtatagtcttggggcccttcaagctgtgaaattgtccttgtactctcagctcctgcatggatctgggtcaagtagaaggtactggggatggggacattcctgcccataaaggatttggggaaagaagattaatcctaaaatacaggtgtgttccatctgaattgaaaatgatatatttgagatataattttaggactggttctgtgtagatagagatggtgtcaaggaggtgcaggatggagatgggagatttcatggagcctggtcagccagctctgtaccaggttgaacaccgaggagctgtcaaagtatttggagtttcttcattgtaaggagtaagggcttccaagatggggcaggtagtccgtacagcctaccaggaacatgttgtgttttctttattttttaaaatcattatattgagttgtgttttcagcactatattggtcaagatagccaagcagtttgtataatttctgtcactagtgtcatacagttttctggtcaacatgtgtgatctttgtgtctcctttttgccaagcacattctgattttcttgttggaacacaggtctagtttctaaaggacaaattttttgttccttgtcttttttctgtaatcctgcaccccagtccaataagcagataccacttaagataggagtctaaactccacagaaaaggataataccaagagcttgtattgttaccttagtcacttgcctagcagtgtgtggctttaaaaactagagatttttcagtcttagtctgcaaactggcatttccgattttccagcataaaaatccacctgtgtctgctgaatgtgtatgtatgtgctcactgtggctttagattctgtccctggggttagccctgttggccctgacaggaagggaggaagcctggtgaatttagtgagcagctggcctgggtcacagtgacctgacctcaaaccagcttaaggctttaagtcctcggttcagtgtagccactctgggctcatagggacacttggtcactccagagtttttaatagctcccaggaggtgatattattttcagtgctcagctgaaataccaaccccaggaataagaactccatttcaaacagttctggccattctgagcctgcttttgtgattgctcatccattgtcctccactagaggggctaagcttgactgcccttagccaggcaagcacagtaatgtgtgttttgttcagcattattatgcaaaaattcactagttgagatggtttgttttaggataggaaatgaaattgcctctcagtgacaggagtggcccgagcctgcttcctattttgattttttttttttttaactgatagatggtgcagcatgtctacatggttgtttgttgctaaactttatataatgtgtggtttcaattcagcttgaaaaataatctcactacatgtagcagtacattatatgtacattatatgtaatgttagtatttctgctttgaatccttgatattgcaatggaattcctactttattaaatgtatttgatatgctagttattgtgtgcgatttaaactttttttgctttctccctttttttggttgtgcgctttcttttacaacaagcctctagaaacagatagtttctgagaattactgagctatgtttgtaatgcagatgtacttagggagtatgtaaaataatcattttaacaaaagaaatagatatttaaaatttaatactaactatgggaaaagggtccattgtgtaaaacatagtttatctttggattcaatgtttgtctttggttttacaaagtagcttgtattttcagtattttctacataatatggtaaaatgtagagcaattgcaatgcatcaataaaatgggtaaattttctgacttatgtggctgtttttgacttctgttataggatataaaggggatcaataaatgacatctttgaaagtgaaaa (SEQ ID NO: 617)Nuak2 gtgctttactgcgcgctctggtactgctgtggctccccgtcctggtgcgggacctgtgcNM_030952 NM_ cccgcgcttcagccctccccgcacagcctactgattcccctgccgcccttgctcacct001195025 cctgctcgccatggagtcgctggttttcgcgcggcgctccggccccactccctcggccgcagagctagcccggccgctggcggaagggctgatcaagtcgcccaagcccctaatgaagaagcaggcggtgaagcggcaccaccacaagcacaacctgcggcaccgctacgagttcctggagaccctgggcaaaggcacctacgggaaggtgaagaaggcgcgggagagctcggggcgcctggtggccatcaagtcaatccggaaggacaaaatcaaagatgagcaagatctgatgcacatacggagcgagattgagatcatgtcatcactcaaccaccctcacatcattgccatccatgaagtgtttgagaacagcagcaagatcgtgatcgtcatggagtatgccagccggggcgacctttatgactccatcagcgagcggcagcagctcagtgagcgcgaagctaggcatttcttccggcagatcgtctctgccgtgcactattgccatcagaacagagttgtccaccgagatctcaagctggagaacatcctcttggatgccaatgggaatatcaagattgctgacttcggcctctccaacctctactatcaaggcaagttcctgcagacattctgtgggagccccctctatgcctcgccagagattgtcaatgggaagccctacacaggcccagaggtggacagctggtccctgggtgttctcctctacatcctggtgcatggcaccatgccctttgatgggcatgaccataagatcctagtgaaacagatcagcaacggggcctaccgggagccacctaaaccctctgatgcctgtggcctgatccggtggctgttgatggtgaaccccacccgccgggccaccctggaggatgtggccagtcactggtgggtcaactggggctacgccacccgagtgggagagcaggaggctccgcatgagggtgggcaccctggcagtgactctgcccgcgcctccatggctgactggctccggcgttcctcccgccccctcctggagaatggggccaaggtgtgcagcttcttcaagcagcatgcacctggtgggggaagcaccacccctggcctggagcgccagcattcgctcaagaagtcccgcaaggagaatgacatggcccagtctctccacagtgacacggctgatgacactgcccatcgccctggcaagagcaacctcaagctgccaaagggcattctcaagaagaaggtgtcagcctctgcagaaggggtacaggaggaccctccggagctcagcccaatccctgcgagcccagggcaggctgccccgctgctccccaagaagggcattctcaagaagccccgacagcgcgagtctggctactactcctctcccgagcccagtgaatctggggagctcttggacgcaggcgacgtgtttgtgagtggggatcccaaggagcagaagcctccgcaagcttcagggctgctcctccatcgcaaaggcatcctcaaactcaatggcaagttctcccagttcagccttggagctcgcggcccccaccaccttcggctccctggatgaactcgccccacctcgccccctggcccgggccagccgaccctcaggggctgtgagcgaggacagcatcctgtcctctgagtcctttgaccagctggacttgcctgaacggctcccagagcccccactgcggggctgtgtgtctgtggacaacctcacggggcttgaggagcccccctcagagggccctggaagctgcctgaggcgctggcggcaggatcctttgggggacagctgcttttccctgacagactgccaggaggtgacagcgacctaccgacggtcaggctctcagatgcagctggttgcaccccgaggggagatgccttctcccccacctcccaggacctgcatcccagctcagaaggctcagttgggtttgcagtggagccctgagcagggctggatatgggaagtaggcaaatgaaatgcgccaagggttcagtgtctgtcttcagccctgctgaacgaagaggatactaaagagaggggaacgggaatgcccgcgacagagtccacattgcctgtttcttgtgtacatgggggggccacagagacctggaaagagaactctcccagggcccatctcctgcatcccatgaatactctgtacacatggtgccttctaaggacagctccttccctactcattccctgcccaagtggggccagacctctttacacacacattcccgttcctaccaaccaccagaactggatggtggcacccctaatgtgcatgaggcatcctgggaatggtctggagtaacgcttcgttatttttatttttatttttatttatttatttatttttttgagacggagtttcgctcttggtgcccaggctagagtgcaatggcgcgatctcagctcacctcaacctccgcctcccgggttcaagcgattctcctgcctcagcctccctagtagctgggattacaggcgcccgccaccatgcccggctaattttgtatttttagtagagacagggtttctccatgttggtcaggctggtctcaaactcccgacctcaggtgatccacccacctcggcctcccaaagtgctgggattacaggcgtgagccaccgcgccccacctaacccttccttatttagcctaggagtaagagaacacaatctctgtttcttcaatggttctcttcccttttccatcctccaaacctggcctgagcctcctgaagttgctgctgtgaatctgaaagacttgaaaagcctccgcctgctgtgtggacttcatctcaaggggcccagcctcctctggactccaccttggacctcagtgactcagaacttctgcctctaagctgctctaaagtccagactatggatgtgttctctaggccttcaggactctagaatgtccatatttatttttatgttcttggctttgtgttttaggaaaagtgaatcttgctgttttcaataatgtgaatgctatgttctgggaaaatccactatgacatctaagttttgtgtacagagagatatttttgcaactatttccacctcctcccacaaccccccacactccactccacactcttgagtctctttacctaaiggtctctacctaatggacctccgtggccaaaaagtaccattaaaaccagaaaggtgattggaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaa (SEQ ID NO: 618) Alkagctgcaagtggcgggcgcccaggcagatgcgatccagcggctctgggggcggc NM_004304NM_007439 agcggtggtagcagctggtacctcccgccgcctctgttcggagggtcgcggggcaccgaggtgctttccggccgccctctggtcggccacccaaagccgcgggcgctgatgatgggtgaggagggggcggcaagatttcgggcgcccctgccctgaacgccctcagctgctgccgccggggccgctccagtgcctgcgaactctgaggagccgaggcgccggtgagagcaaggacgctgcaaacttgcgcagcgcgggggctgggattcacgcccagaagttcagcaggcagacagtccgaagccttcccgcagcggagagatagcttgagggtgcgcaagacggcagcctccgccctcggttcccgcccagaccgggcagaagagcttggaggagccaaaaggaacgcaaaaggcggccaggacagcgtgcagcagctgggagccgccgttctcagccttaaaagttgcagagattggaggctgccccgagaggggacagaccccagctccgactgcggggggcaggagaggacggtacccaactgccacctcccttcaaccatagtagttcctctgtaccgagcgcagcgagctacagacgggggcgcggcactcggcgcggagagcgggaggctcaaggtcccagccagtgagcccagtgtgcttgagtgtctctggactcgcccctgagcttccaggtctgtttcatttagactcctgctcgcctccgtgcagttgggggaaagcaagagacttgcgcgcacgcacagtcctctggagatcaggtggaaggagccgctgggtaccaaggactgttcagagcctcttcccatctcggggagagcgaagggtgaggctgggcccggagagcagtgtaaacggcctcctccggcgggatgggagccatcgggctcctgtggctcctgccgctgctgctttccacggcagctgtgggctccgggatggggaccggccagcgcgcgggctccccagctgcggggccgccgctgcagccccgggagccactcagctactcgcgcctgcagaggaagagtctggcagttgacttcgtggtgccctcgctcttccgtgtctacgcccgggacctactgctgccaccatcctcctcggagctgaaggctggcaggcccgaggcccgcggctcgctagctctggactgcgccccgctgctcaggttgctggggccggcgccgggggtctcctggaccgccggttcaccagccccggcagaggcccggacgctgtccagggtgctgaagggcggctccgtgcgcaagctccggcgtgccaagcagttggtgctggagctgggcgaggaggcgatcttggagggttgcgtcgggccccccggggaggcggctgtggggctgctccagttcaatctcagcgagctgttcagttggtggattcgccaaggcgaagggcgactgaggatccgcctgatgcccgagaagaaggcgtcggaagtgggcagagttgggaaggctgtccgcggcaattcgcgcctcccagccccgccttctcttccagatcttcgggactggtcatagctccttggaatcaccaacaaacatgccttctccttctcctgattattttacatggaatctcacctggataatgaaagactccttccctttcctgtctcatcgcagccgatatggtctggagtgcagctttgacttcccctgtgagctggagtattcccctccactgcatgacctcaggaaccagagctggtcctggcgccgcatcccctccgaggaggcctcccagatggacttgctggatgggcctggggcagagcgttctaaggagatgcccagaggctcctttctccttctcaacacctcagctgactccaagcacaccatcctgagtccgtggatgaggagcagcagtgagcactgcacactggccgtctcggtgcacaggcacctgcagccctctggaaggtacattgcccagctgctgccccacaacgaggctgcaagagagatcctcctgatgcccactccagggaagcatggttggacagtgctccagggaagaatcggccgtccagacaacccatttcgagtggccctggaatacatctccagtggaaaccgcagcttgtctgcagtggacttctttgccctgaagaactgcagtgaaggaacatccccaggctccaagatggccctgcagagctccttcacttgttggaatgggacagtcctccagcttgggcaggcctgtgacttccaccaggactgtgcccagggagaagatgagagccagatgtgccggaaactgcctgtgggtttttactgcaactttgaagatggcttctgtggctggacccaaggcacactgtcaccccacactcctcaatggcaggtcaggaccctaaaggatgcccggttccaggaccaccaagaccatgctctattgctcagtaccactgatgtccccgcttctgaaagtgctacagtgaccagtgctacgtttcctgcaccgatcaagagctctccatgtgagctccgaatgtcctggctcattcgtggagtcttgaggggaaacgtgtccttggtgctagtggagaacaaaaccgggaaggagcaaggcaggatggtctggcatgtcgccgcctatgaaggcttgagcctgtggcagtggatggtgttgcctctcctcgatgtgtctgacaggttctggctgcagatggtcgcatggtggggacaaggatccagagccatcgtggcttttgacaatatctccatcagcctggactgctacctcaccattagcggagaggacaagatcctgcagaatacagcacccaaatcaagaaacctgtttgagagaaacccaaacaaggagctgaaacccggggaaaattcaccaagacagacccccatctttgaccctacagttcattggctgttcaccacatgtggggccagcgggccccatggccccacccaggcacagtgcaacaacgcctaccagaactccaacctgagcgtggaggtggggagcgagggccccctgaaaggcatccagatctggaaggtgccagccaccgacacctacagcatctcgggctacggagctgctggcgggaaaggcgggaagaacaccatgatgcggtcccacggcgtgtctgtgctgggcatcttcaacctggagaaggatgacatgctgtacatcctggttgggcagcagggagaggacgcctgccccagtacaaaccagttaatccagaaagtctgcattggagagaacaatgtgatagaagaagaaatccgtgtgaacagaagcgtgcatgagtgggcaggaggcggaggaggagggggtggagccacctacgtatttaagatgaaggatggagtgccggtgcccctgatcattgcagccggaggtggtggcagggcctacggggccaagacagacacgttccacccagagagaccaggagaataactcctcggttctagggctaaacggcaattccggagccgcaggtggtggaggtggctggaatgataacacttccttgctctgggccggaaaatctttgcaggagggtgccaccggaggacattcctgccctcaggccatgaagaagtgggggtgggagacaagagggggtttcggagggggtggaggggggtgctcctcaggtggaggaggcggaggatatataggcggcaatgcagcctcaaacaatgaccccgaaatggatggggaagatggggtttccttcatcagtccactgggcatcctgtacaccccagctttaaaagtgatggaaggccacggggaagtgaatattaagcattatctaaactgcagtcactgtgaggtagacgaatgtcacatggaccctgaaagccacaaggtcatctgcttctgtgaccacgggacggtgctggctgaggatggcgtctcctgcattgtgtcacccaccccggagccacacctgccactctcgctgatcctctctgtggtgacctctgccctcgtggccgccctggtcctggcattctccggcatcatgattgtgtaccgccggaagcaccaggagctgcaagccatgcagatggagctgcagagccctgagtacaagctgagcaagctccgcacctcgaccatcatgaccgactacaaccccaactactgctttgctggcaagacctcctccatcagtgacctgaaggaggtgccgcggaaaaacatcaccttcattcggggtctgggccatggcgcctttggggaggtgtatgaaggccaggtgtccggaatgcccaacgacccaagccccctgcaagtggctgtgaagacgctgcctgaagtgtgctctgaacaggacgaactggatttcctcatggaagccctgatcatcagcaaattcaaccaccagaacattgttcgctgcattggggtgagcctgcaatccctgccccggttcatcctgctggagctcatggcggggggagacctcaagtccttcctccgagagacccgccctcgcccgagccagccctcctccctggccatgctggaccttctgcacgtggctcgggacattgcctgtggctgtcagtatttggaggaaaaccacttcatccaccgagacattgctgccagaaactgcctcttgacctgtccaggccctggaagagtggccaagattggagacttcgggatggcccgagacatctacagggcgagctactatagaaagggaggctgtgccatgctgccagttaagtggatgcccccagaggccttcatggaaggaatattcacttctaaaacagacacatggtcctttggagtgctgctatgggaaatcttttctcttggatatatgccataccccagcaaaagcaaccaggaagttctggagtttgtcaccagtggaggccggatggacccacccaagaactgccctgggcctgtataccggataatgactcagtgctggcaacatcagcctgaagacaggcccaactttgccatcattttggagaggattgaatactgcacccaggacccggatgtaatcaacaccgctttgccgatagaatatggtccacttgtggaagaggaagagaaagtgcctgtgaggcccaaggaccctgagggggttcctcctctcctggtctctcaacaggcaaaacgggaggaggagcgcagcccagctgccccaccacctctgcctaccacctcctctggcaaggctgcaaagaaacccacagctgcagagatctctgttcgagtccctagagggccggccgtggaagggggacacgtgaatatggcattctctcagtccaaccctccttcggagttgcacaaggtccacggatccagaaacaagcccaccagcttgtggaacccaacgtacggctcctggtttacagagaaacccaccaaaaagaataatcctatagcaaagaaggagccacacgacaggggtaacctggggctggagggaagctgtactgtcccacctaacgttgcaactgggagacttccgggggcctcactgctcctagagccctcttcgctgactgccaatatgaaggaggtacctctgttcaggctacgtcacttcccttgtgggaatgtcaattacggctaccagcaacagggcttgcccttagaagccgctactgcccctggagctggtcattacgaggataccattctgaaaagcaagaatagcatgaaccagcctgggccctgagctcggtcgcacactcacttctcttccttgggatccctaagaccgtggaggagagagaggcaatggctccttcacaaaccagagaccaaatgtcacgttttgttttgtgccaacctattttgaagtaccaccaaaaaagctgtattttgaaaatgctttagaaaggttttgagcatgggttcatcctattctttcgaaagaagaaaatatcataaaaatgagtgataaatacaaggcccagatgtggttgcataaggtttttatgcatgtttgttgtatacttccttatgcttctttcaaattgtgtgtgtctgcttcaatgtagtcagaattagctgcttctatgtttcatagttggggtcatagatgtttccttgccttgttgatgtggacatgagccatttgaggggagagggaacggaaataaaggagttatttgtaatgactaaaa (SEQ ID NO: 619) Pdzk1ip1gcccgtcttcgtgtctcctccctccctcgccttcctccttcctagctcctctcctccaggg NM_005764NM_ ccagactgagcccaggttgatttcaggcggacaccaatagactccacagcagctcca 001164557ggagcccagacaccggcggccagaagcaaggctaggagctgctgcagccatgtcggccctcagcctcctcattctgggcctgctcacggcagtgccacctgccagctgtcagcaaggcctggggaaccttcagccctggatgcagggccttatcgcggtggccgtgttcctggtcctcgttgcaatcgcctttgcagtcaaccacttctggtgccaggaggagccggagcctgcacacatgatcctgaccgtcggaaacaaggcagatggagtcctggtgggaacagatggaaggtactcttcgatggccgccagtttcaggtccagtgagcatgagaatgcctatgagaatgtgcccgaggaggaaggcaaggtccgcagcaccccgatgtaaccttctctgtggctccaaccccaagactcccaggcacatgggatggatgtccagtgctaccacccaagccccctccttctttgtgtggaatctgcaatagtgggctgactccctccagccccatgccggccctacccgcccagaagtatagccagccaaggttggagctcagaccgtgtctaggttggggctcggctgtggccctggggtctcctgctcagctcagaagagccttctggagaggacagtcagctgagcacctcccatcctgctcacacgtccttccccataactatggaaatggccctaatttctgtgaaataaagactttttgtatttctggggctgaggctcagcaacagcccctcaggcttccagtga (SEQ ID NO: 620) lnpp5baaatgtagtcactgtcccggaacctggggcagcggagtcccgtgcgccctgtggtg NM_005540NM_008385 acagctcaggagggtgtgtgcgctcagcaggggccagcatggaccagtctgtggcaatccaggagacgctggctgagggggaatactgcgtcatcgcggtgcaaggtgtgcggagcacggcggccaggaacacgctctcttcctctatacgcaccggaggatggccattaccggggacgatgtctctctggaccagatagtgccagtctcgcgggattttacgctggaagaagtgtccccagatggtgaactctacatccttggacagatgtgaccgtccagctggacacagcagagcttttgcctcgtattccaactgccctttggttcacaaaccaggatgttcctccacgaagttgccagggcctgtccaggcttcgattctgcgacccgggatcctgaattcctgtggctgtctcggtataggtgcgcagagctggagctggagatgccaacgccgcgcggttgtaactcggccctagttacctggccagggtacgcgacaattggcggaggtggttctaactttgatggtttgagaccaaatgggaagggagtgcctatggaccaaagctccaggggtcaagataaaccagaaagcttgcaaccaagacagaataaatccaagtccgaaattactgacatggttcgctcctccactatcacagtgtcggacaaggctcatattttatccatgcagaagtttggactgcgagatacaattgtgatatcacatctactacagaaagaagaggattacacctatatccagaacttcaggttttttgcgggaacatacaatgtaaatgggcagtcccccaaagaatgcctccggctgtggctgagcaatggtatccaggccccagatgtctattgtgtagggttccaggagcttgatctgagtaaggaagcttttttctttcacgataccccaaaggaggaagagtggttcaaagctgtgtcagagggtcttcatccagatgccaaatatgcaaaggtgaagcttatccgactggttgggattatgctgctgttatatgtcaaacaggagcatgcagcttatatctcagaagtggaagccgagactgtggggacaggaatcatggggaggatgggcaacaagggaggcgtggcgatcaggttccagttccacaacaccagcatctgcgttgtgaattctcacttggcagcccacattcaagagtatgagaggaggaaccaggactataaggacatttgttctcgaatgcagttagtcagcctgacccaagccttccccctctcaccatcagcaaccatgatgtgatcttgtggctgggggacctcaactacaggatagaagagctggatgtggaaaaagtgaaaaagctcatcgaagagaaggactttcaaatgctgtatgcatatgatcagctgaaaattcttggtggccgcaaagactgtctttgaaggcttcacagagggtgagctcacattccagcctacttacagtatgatacgggctctgacgactgggataccagtgagaagtgccgtgctcctgcctggtgtgatcggattctctggaaagggaagaacatcactcagctgagttaccagagccacatggccctgaagaccagtgaccacaagcctgtcagctcagtgtttgacatcggggtgagggtcgtaaatgacgagctttaccggaagacactggaggaaattgttcgctccctggataagatggaaaatgccaacattccttctgtgtccctgtccaagcgagagttctgttttcagaatgtgaagtacatgcaattgaaagtagaatcctttacaattcataatggacaagtaccctgtcattttgaattcatcaacaagcctgatgaagagtcttactgtaagcagtggctgaatgccaaccccagcagaggcttcctcctgccagattctgatgttgagattgacttggagctcttcgtaaataagatgacagctacaaagctcaactcgggtgaagacaaaattgaggacattctggttctgcacttggacaggggaaaggattactttttgtctgtgtctgggaactacctgcccagctgttttgggtctcccattcatacactgtgttacatgagagagccaatcttggacctaccacttgaaaccattagtgagctgactctgatgccagtatggactggagatgatgggagccagttggatagccccatggaaatccccaaagagctctggatgatggttgattacctgtaccgaaatgctgtccagcaggaagatctgtttcagcaaccaggcctgaggtcagaatttgaacatatcagggactgcttggatactggaatgattgataacctctctgccagcaatcattctgtagccgaagccctgctgcttttcctggagagccttccagagcctgtcatctgttacagcacctaccataactgcttggagtgttctggcaactacacagcaagcaaacaggtcatttctactctccccatattccacaaaaatgtcaccactacttgatggcgtttttgcgagaactgctgaaaaattcagcaaaaaatcatttggatgagaatattctagctagcatatttggcagcttattgcttcgaaacccagctggtcaccaaaagcttgatatgacagagaagaagaaggctcaagaatttattcaccagttcctctgcaacccactctgagcctctctctcctcctattttacttgaggctgccaattaccagccccacctgtttcagctcaagagatgccttaagataattatgtgaggccacttggtagcaagaatggcagctatttcctgagcctagtaccccaattaagcccaccattggttagcacactcagcgctgtgagtcgtgaagacacgggagaaaatccaccataataaaactgacattcaattttcaactttagttatttaacacagatttttttattttttatttttttttattttgagacggagttttgctctgtcgcgcagggtggagtgcggtggcacgatctcggctcactgcaacctctgcctcctgggtgcaagcaattatcctgcctcagcctcccgagtagctgggactgcaggcacacactgccacgcccagctaattttttgcattttagtagagacggggtttcaccgtgttgcccaggctgttctaaaactcctgaactcaggtaatctgcctgcctcggcctccccaagtgctaggattacagatgtgagccaccacgcccggccttttttttttttttttcttttttgagatggagtttcactcttgttgcccaggctggagtgcgttggcgtggtcttggctcactgcaacctctgcctctttggttcaagcaattctcctgcctcagcctctcgagtagctgggattataggcgtccgccaccatgcctggctaatttttagtgtgtattagtatagacacggtttcaccatgttggccaggctggtctcgaatgcctggcctcaggtgatccacctgccttggcctcccaaagtgctgggattacaggcatgaaccaccacgcctggcctaaaatgtttttaaataaagtacttgtactcactcaccctacctccagggcatagtcagtctgggctgagatccccatgatcagatatttgatggaaagtcctgaaaggccaatgagttggatggcaagaatgcaggcagaagctgctggataaaataggctacagccacctcagatgctttcagtgctctgtctgaggatgtgtatatgcatatgcaaactcgacccccgttcctgcccagataatggctcaataactctgaggctggttgctcagcctctgagggcaatacaggcatttaaaaaattaaaatgaccaggcacagtggctcacgcctgtaatctcggcactttgggagactgaggtgggagcatcacttgagaccaggagtttgggaccaggctgggcaacacagggagaccccctctctacaaaaacatttttaaaaaattagagggtgtggtgatgcatgcctgtggtcccagttacttgggaggctgacgtgggtggctcacttgagcacaggagtttgaggctgcagtgacctatgaccacatcactgtacgccagcccgggtgagagagggagaccccgtctctaaaaataaaatgtaaaatcactgaaaaaatgagtgttcggtgaaacaagtgggattttctgggccagcaagtcttccaaactgtatatgatgcatcctgtctccatgtgtaatatattttaatgataaatgtatttttaacagtgaaaaaaaaaaaaaaa (SEQ ID NO: 653) Socs1ggcagctgcacggctcctggccccggagcatgcgcgagagccgccccggagcgc NM_003745 NM_cccggagccccccgccgtcccgcccgcggcgtcccgcgctcgccgccagcgca 001271603cccccggacgctatggcccacccctccggctggccccttctgtaggatggtagcacacaaccaggtggcagccgacaatgcagtctccacagcagcagagccccgacggcggccagaaccttcctcctcttcctcctcctcgcccgcggcccccgcgcgcccgcggccgtgccccgcggtcccggtcccggcccccggcgacacgcacttccgcacattccgttcgcacgccgattaccggcgcatcacgcgcgccagcgcgctcctggacgcctgcggattctactgggggcccctgagcgtgcacggggcgcacgagcggctgcgcgccgagcccgtgggcaccttcctggtgcgcgacagccgccagcggaactgctttttcgcccttagcgtgaagatggcctcgggacccacgagcatccgcgtgcactttcaggccggccgctttcacctggatggcagccgcgagagcttcgactgcctcttcgagctgctggagcactacgtggcggcgccgcgccgcatgctgggggccccgctgcgccagcgccgcgtgcggccgctgcaggagctgtgccgccagcgcatcgtggccaccgtgggccgcgagaacctggctcgcatccccctcaaccccgtcctccgcgactacctgagctccttccccttccagatttgaccggcagcgcccgccgtgcacgcagcattaactgggatgccgtgttattttgttattacttgcctggaaccatgtgggtaccctccccggcctgggttggagggagcggatgggtgtaggggcgaggcgcctcccgccctcggctggagacgaggccgcagaccccttctcacctcttgagggggtcctccccctcctggtgctccctctgggtccccctggttgttgtagcagcttaactgtatctggagccaggacctgaactcgcacctcctacctcttcatgtttacatatacccagtatctttgcacaaaccaggggttgggggagggtctctggctttatttttctgctgtgcagaatcctattttatattttttaaagtcagtttaggtaataaactttattatgaaagtttttttttt (SEQ ID NO: 654) Jungacatcatgggctatttttaggggttgactggtagcagataagtgttgagctcgggctg NM_002228NM_010591 gataagggctcagagttgcactgagtgtggctgaagcagcgaggcgggagtggaggtgcgcggagtcaggcagacagacagacacagccagccagccaggtcggcagtatagtccgaactgcaaatcttattttcttttcaccttctctctaactgcccagagctagcgcctgtggctcccggactggtgtttcgggagtgtccagagagcctggtctccagccgcccccgggaggagagccctgctgccatggcgctgttgacagcggcggaaagcagcggtacccacgcgcccgccgggggaagtcggcgagcggctgcagcagcaaagaactttcccggctgggaggtccggagacaagtggcagttgtcccggagcgaacgtttgcaagcctttcctgcgtcttaggcttctccacggcggtaaagaccagaaggcggcggagagccacgcaagagaagaaggacgtgcgctcagcttcgctcgcaccggttgttgaacttgggcgagcgcgagccgcggctgccgggcgccccctccccctagcagcggaggaggggacaagtcgtcggagtccgggcggccaagacccgccgccggccggccactgcagggtccgcactgatccgctccgcggggagagccgctgctctgggaagtgagttcgcctgcggactccgaggaaccgctgcgcccgaagagcgctcagtgagtgaccgcgacttttcaaagccgggtagcgcgcgcgagtcgacaagtaagagtgcgggaggcatcttaattaaccctgcgctccctggagcgagctggtgaggagggcgcagcggggacgacagccagcgggtgcgtgcgctcttagagaaactttccctgtcaaaggctccggggggcgcgggtgtcccccgcttgccagagccctgttgcggccccgaaacttgtgcgcgcagcccaaactaacctcacgtgaagtgacggactgttctatgactgcaaagatggaaacgaccttctatgacgatgccctcaacgcctcgttcctcccgtccgagagcggaccttatggctacagtaaccccaagatcctgaaacagagcatcaccctgaacctggccgacccagtgggagcctgaagccgcacctccgcgccaagaactcggacctcctcacctcgcccgacgtggggctgctcaagctggcgtcgcccgagctggagcgcctgataatccagtccagcaacgggcacatcaccaccacgccgacccccacccagttcctgtgccccaagaacgtgacagatgagcaggagggcttcgccgagggcttcgtgcgcgccctggccgaactgcacagccagaacacgctgcccagcgtcacgtcggcggcgcagccggtcaacggggcaggcatggtggctcccgcggtagcctcggtggcagggggcagcggcagcggcggcttcagcgccagcctgcacagcgagccgccggtctacgcaaacctcagcaacttcaacccaggcgcgctgagcagcggcggcggggcgccctcctacggcgcggccggcctggcctttcccgcgcaaccccagcagcagcagcagccgccgcaccacctgccccagcagatgcccgtgcagcacccgcggctgcaggccctgaaggaggagcctcagacagtgcccgagatgcccggcgagacaccgcccctgtcccccatcgacatggagtcccaggagcggatcaaggcggagaggaagcgcatgaggaaccgcatcgctgcctccaagtgccgaaaaaggaagctggagagaatcgcccggctggaggaaaaagtgaaaaccttgaaagctcagaactcggagctggcgtccacggccaacatgctcagggaacaggtggcacagcttaaacagaaagtcatgaaccacgttaacagtgggtgccaactcatgctaacgcagcagttgcaaacattttgaagagagaccgtcgggggctgaggggcaacgaagaaaaaaaataacacagagagacagacttgagaacttgacaagttgcgacggagagaaaaaagaagtgtccgagaactaaagccaagggtatccaagttggactgggttgcgtcctgacggcgcccccagtgtgcacgagtgggaaggacttggcgcgccctcccttggcgtggagccagggagcggccgcctgcgggctgccccgctttgcggacgggctgtccccgcgcgaacggaacgttggacttttcgttaacattgaccaagaactgcatggacctaacattcgatctcattcagtattaaaggggggagggggagggggttacaaactgcaatagagactgtagattgcttctgtagtactccttaagaacacaaagcggggggagggttggggaggggcggcaggagggaggtttgtgagagcgaggctgagcctacagatgaactctttctggcctgccttcgttaactgtgtatgtacatatatatattttttaatttgatgaaagctgattactgtcaataaacagcttcatgcctttgtaagttatttcttgtttgtttgtttgggtatcctgcccagtgttgtttgtaaataagagatttggagcactctgagtttaccatttgtaataaagtatataatttttttatgttttgtttctgaaaattccagaaaggatatttaagaaaatacaataaactattggaaagtactcccctaacctcttttctgcatcatctgtagatactagctatctaggtggagttgaaagagttaagaatgtcgattaaaatcactctcagtgcttcttactattaagcagtaaaaactgttctctattagactttagaaataaatgtacctgatgtacctgatgctatggtcaggttatactcctcctcccccagctatctatatggaattgcttaccaaaggatagtgcgatgtttcaggaggctggaggaaggggggttgcagtggagagggacagcccactgagaagtcaaacacttcaaagtttggattgtatcaagtggcatgtgctgtgaccatttataatgttagtagaaattaacaataggtgcttattctcaaagcaggaattggtggcagattttacaaaagatgtatccttccaatttggaatcttctctttgacaattcctagataaaaagatggcctttgcttatgaatatttataacagcattcttgtcacaataaatgtattcaaataccaaaaaaaaaaaaaaaaa (SEQ ID NO: 655) Nptxrcggccgcggcgacagctccagctccggctccggctccggctccggctccggctcc NM_014293NM_030689 cgcgcctgccccgctcggcccagcgcgcctgggctccgcgccccgaccccgtcgccgcgcctgccgggggcctcgggcgcccccgccgcccgcctcacgctgaagttcctggccgtgctgctggccgcgggcatgctggcgttcctcggtgccgtcatctgcatcatcgccagcgtgcccctggcggccagcccggcgcgggcgctgcccggcggcgccgacaatgcttcggtcgcctcgggcgccgccgcgtccccgggcccgcagcggagcctgagcgcgctgcacggcgcgggcggttcagccgggccccccgcgctgcccggggcacccgcggccagcgcgcacccgctgccgcccgggcccctgttcagccgcttcctgtgcacgccgctggagctgcctgcccgtcgggggcccagcagggggacgcggcgggcgctgcgccgggcgagcgcgaagagctgctgctgctgcagagcacggccgagcagctgcgccagacggcgctgcagcaggaggcgcgcatccgcgccgaccaggacaccatccgtgagctcaccggcaagctgggccgctgcgagagcggcctgccgcgcggcctccagggcgccgggccccgccgcgacaccatggccgacgggccctgggactcgcctgcgctcattctggagctggaggacgccgtgcgcgccctgcgggaccccatcgaccgcctggagcaggagcttccagcccgtgtgaacctctcagctgccccagccccagtctctgctgtgcccaccggcctacactccaagatggaccagctggaggggcagctgctggcccaggtgctggcactggagaaggagcgtgtggccctcagccacagcagccgccggcagaggcaggaagtggaaaaggagttggacgtcctgcagggtcgtgtggctgagctggagcacgggtcctcagcctacagtcctccagatgccttcaagatcagcatccccatccgtaacaactacatgtacgcccgcgtgcggaaggctctgcccgagctctacgcattcaccgcctgcatgtggctgcggtccaggtccagcggcaccggccagggcacccccttctcctactcagtgcccgggcaggccaacgagattgtactgctagaggcgggccatgagcccatggagctgctgatcaacgacaaggtggcccagctgcccctgagcctgaaggacaatggctggcaccacatctgcatcgcctggaccacaagggatggcctatggtctgcctaccaggacggggagctgcagggctccggtgagaacctggctgcctggcaccccatcaagcctcatgggatccttatcttgggccaggagcaggataccctgggtggccggtttgatgccacccaggcctttgtcggtgacattgcccagtttaacctgtgggaccacgccctgacaccagcccaggtcctgggcattgccaactgcactgcgccactgctgggcaacgtccttccctgggaagacaagttggtggaggcctttgggggtgcaacaaaggctgccttcgatgtctgcaaggggagggccaaggcatgaggggccacctcatccagggcccctcccttgcctgccactttggggacttgaggggggtcatattccctcctcagcctgcccacgcactggccttccctcctgccccactcctggctgtgcctcccatttcccctcacctgtacccacacctccagaatgccctgccctgcgagtgtgtcccctgtccccacctgagtggggaggagcgtctcaagtgaacagtgggagcctgcccacctggcactgcactggagttgtctcttaccccaccctccctgcccatcaactgtatctgatttcactaattttgacagcacccccagtagggtaggattgtgtatgagggggaccccactatctcagtggtgggggtggccgcccgcccccttgtcccccatgcaacaggcccagtggcttccccttcagggcatcaacaggctgtagaaggggatgacgaggacatcagttggttagacttttccctcctccctctttccaccagctgccagtcttagggcagtgggatctcgatggagcctccccccccccccacccatgcctccctcttcctcctctttcctcctctctttgtgtgtagcggtttgaatgttggttccatgcctggcccagccccacctcagtctccaggacattcctttcccagctccagcctggagggaaggggacaaagaccccaggaggccaaagggctgcagtcaccccttgtgctcacccatagtgatggccactggtatagtcatcgctctccctccatgccaaggacaggaatggaccgcttcagcctgggctgggagcagccctaaggtagaggcctcatggcccaggagaccccacctctggcagagccacattacctaccctgtgcatggtcctggggcagcaaggaagaagctcagagggtggggagaagcatgaagcagtgagcagagcactgggtgagagggagaagaccttggttcctagccagccctgctaatgtgctgtgtggccttctgtaagtccctgccctctctgggcctggccttcctcattcgtgagctgaggccctcgctttggtcatttgctctccagattgggtgtgagcttctctgtgaaccaggtggatatgtggggaaagctctggtgaccctgggcttcgcaggggtagatcccaggactcggcagtggatgggatgcagccagtcatgggttagggtcagcagagactcagagtccagggcaaggttcaaggcagactaacctcatgcatggattgtaaaaaaccagctccctttggatcaacccagcctggcacccttgcctgtctgagagtgtctcaaagggctgatggcttcctggtccccttgagtcatcaccagcttccccaagagagtgtcagaatcttaagagctgagaggccgggcacggtggctcacgcctgtaatcccagcactttgggaggctgagacaggcagatcacttgaggtcaggagttcgaagtcagcctggccaacgtggtgaaaccccatcttcactaaaaatacaaaacttagctggttaggtggtgcatgcctgtagtcccagctactcgggaggccgaggcagaagaatctcttgaactgaggaggtggaggttgcagtgagccgagatcacgccattgcactccagcctgggcaacagagcaagaaccatctcaaaaaaataataataatcttaaagatgagaaaagccaccccatctggcaccacagctgcatcttgcttgtgagaaatggggaagagttcagggaggacacgtgacctgcacaggatcacagagcatggggcagagccaggactagagctcagggcatctgactccctcttcagtgttcttccccctccatgttgcctgcccctgaagacctttgagttcagtctacacctaagcaggtagacatccgcgaggtcagatgctttccaacatgacacctgaacatcttcctttatgcaacacccaaacatcttggcatccccaccccaggaagtgcggggaggaggttatgatccctgggcgcttcggcagaatggagagctgaggtgtccctcccctgctagtcacctaccaggtgtctgagcagctgcatgctccctggctcaagtgggcactgtaccttttgcctgcctttttgttccctatctccactccctgaggccacttagcctgagacatgatgcaagagctgcaggccggggggctcagtgccatggaagctactccaagttgcattgcctcccgcgcccagatcctgctttccatttcgagaacataaatagattgcccagcccctccagtacaatcccactggaagaaaaggcaatggcgggcttcagccagacctgctgagacctaggttgccacggtaacagccaaagacatcaacccaagtgctgggtcaagtgtctcatcatactggcactgttgctggggtgacggcagaattcagaacttcaatttcagtgacgccaagcttgatgtgtttctgttattgttttgaagaaggtagctcttgtggaggacttgggagaaggatggggtcttaggaaggaggtgacagcacttgcatggtcacttgagcccacacacacgctcaaccccaagtcctttatgctttgtcacagtgaagatgagacctctgacgtccaagccttgttcctgtgctgcatcacccactcagctttccaaagggaacaggaacaaatttccccagcaccactgtttgggtcccgcttttcctatcttctgctgcccctgagcacatccaagcagacagggaaagaggagtcagacatggcccagtcacatcctgagctgctcctggctgataaccacgatggagcccgtgtttgtcctgccatctggcactgcactgagtgtggcacaggcaccgtcctgttgatctcacaacacagttctaagttaggacgttcttggctccgttagacaggtgaggaaactggggcacagagaggtgatgtcatctgcctggtgtatatcagctagcaagtgatggagcccagatttcaaaccaaagggggttacgtccaggggctgagttcccactcacctgtgtagagtgccatctgggcaccattgctccagacgtgttccgacccctttcccagcccacagggcttgaagtgaaggaacagaggcagcgggtgggccagccccagggccagggtccccttggtgaagccgtgccagggggctcagctgcttcagggaatgtgtccctcccaccatgggccagagcttcagcccttctttagctcagctagagttcacaggagagccaaaaaagaaaaggaagagagcatctcccgagtcctgggcagggaaggggagggaaattgctgcttctccaactcttgcttggggccaagccctgcaccagttgcttcccagctgttatctgccagatcttcccatcttgtggcatgtggtgcccccaccaacatcccaaggggaccaatccccttgccaccactttgcatcacctgggaccacagatttggacaggaagggctctgagaagaggccaaagccctcattttacagatgaggaagctgaagcccggggaggggagcgaccctcaaggccacccagctggacacgggagacttgagcccagccttctgactgcattcagccctctctaggacgcagcagcctctccccagcactgagtcccccctcctttgtgtgtcccagcacccttggcctgagtaaacttggaaaggggctccctcccagagaagggactactctcttcacccctttattccagctgcctgccaccccagacccccacctcccaccctgacccccgacccctgggtggggaaggggctcacatgggcccaggctgagtgtgagtgagcatgtcaagttgtctgacactgtgacattagtgcaccctactgacaacccctccccagccttgcccctttctcctctccctgttttgtacataaattgttatgagctgcaacatgtgtgcgtgtgtgtgcgtgtgtgtgtgtgtgtatgtgtgtgtgatctgtgtcatggttttgttacctttttgtttttgtaaacttgaatgttcaaaataaacatgctgtttactctgagaaaaaaaaaaaaaaaa (SEQ ID NO: 656) Socs3gcggctcccgacttggactccctgctccgctgctgccgcttcggccccgcacgcagcc NM_003955NM_007707 gcggctccgacttggactccctgctccgctgctgccgcttcggccccgcacgcagccagccgccagccgcccgcccggcccagctcccgccgcggccccttgccgcggtccctctcctggtcccctcccggttggtccgggggtgcgcagggggcagggcgggcgcccaggggaagctcgagggacgcgcgcgcgaaggctcctttgtggacttcacggccgaaacatctgggcgcagcgcgggccaccgctggccgtctcgccgccgcgtcgccttggggacccgagggggctcagccccaaggacggagacttcgattcgggaccagccccccgggatgcggtagcggccgagtgcggaggccgcgaagcagagcagccgccgccgcgcagatccacgctggctccgtgcgccatggtcacccacagcaagtttcccgccgccgggatgagccgccccctggacaccagcctgcgcctcaagaccttcagctccaagagcgagtaccagctggtggtgaacgcagtgcgcaagctgcaggagagcggatctactggagcgcagtgaccggcggcgaggcgaacctgctgctcagtgccgagcccgccggcacctttctgatccgcgacagctcggaccagcgccacttcttcacgctcagcgtcaagacccagtctgggaccaagaacctgcgcatccagtgtgaggggggcagcttctctctgcagagcgatccccggagcacgcagcccgtgccccgcttcgactgcgtgctcaagctggtgcaccactacatgccgccccctggagccccctccttcccctcgccacctactgaaccctcctccgaggtgcccgagcagccgtctgcccagccactccctcggagtccccccagaagagcctattacatctactccgggggcgagaagatccccctggtgttgagccggcccctctcctccaacgtggccactcttcagcatctctgtcggaagaccgtcaacggccacctggactcctatgagaaagtcacccagctgccggggcccattcggcagttcctggaccagtacgatgccccgctttaaggggtaaagggcgcaaagggcatgggtcgggagaggggacgcaggcccctctcctccgtggcacatggcacaagcacaagaagccaaccaggagagagtcctgtagctctggggggaaagagggcggacaggcccctccctctgccctctccctgcagaatgtggcaggcggacctggaatgtgttggagggaagggggagtaccacctgagtctccagcttctccggaggagccagctgtcctggtgggacgatagcaaccacaagtggattctccttcaattcctcagcttcccctctgcctccaaacaggggacacttcgggaatgctgaactaatgagaactgccagggaatcttcaaactttccaacggaacttgtttgctctttgatttggtttaaacctgagctggttgtggagcctgggaaaggtggaagagagagaggtcctgagggccccagggctgcgggctggcgaaggaaatggtcacaccccccgcccaccccaggcgaggatcctggtgacatgctcctctccctggctccggggagaagggcttggggtgacctgaagggaaccatcctggtaccccacatcctctcctccgggacagtcaccgaaaacacaggttccaaagtctacctggtgcctgagagcccagggcccttcctccgttttaagggggaagcaacatttggaggggatggatgggctggtcagctggtctccttttcctactcatactataccttcctgtacctgggtggatggagcgggaggatggaggagacgggacatctttcacctcaggctcctggtagagaagacaggggattctactctgtgcctcctgactatgtctggctaagagattcgccttaaatgctccctgtcccatggagagggacccagcataggaaagccacatactcagcctggatgggtggagaggctgagggactcactggagggcaccaagccagcccacagccagggaagtggggagggggggcggaaacccatgcctcccagctgagcactgggaatgtcagcccagtaagtattggccagtcaggcgcctcgtggtcagagcagagccaccaggtcccactgccccgagccctgcacagccctccctcctgcctgggtgggggaggctggaggtcattggagaggctggactgctgccaccccgggtgctcccgctctgccatagcactgatcagtgacaatttacaggaatgtagcagcgatggaattacaggaacagttttttgtttttgtttttgtttttgtttttgtgggggggggcaactaaacaaacacaaagtattctgtgtcaggtattgggctggacagggcagttgtgtgttggggtggtttttttctctattttatgtttgtttcttgttattaataatgtttacaatctgcctcaatcactctgtcttttataaagattccacctccagtcctctctcctcccccttactcaggcccttgaggctattaggagatgcttgaagaactcaacaaaatcccaatccaagtcaaactttgcacatatttatatttatattcagaaaagaaacatttcagtaatttataataaagagcactattttttaatgaaaaac(SEQ ID NO: 657) F1lrgaggcagctcctgtggggaaaggcgccagtgcgccgaggcggggagtggcggc NM_016946NM_172647 gaggcagctcctgtggggaaaggcgccagtgcgccgaggcggggagtggcggcggggtaacacctggccgaggtgactcgttctgaagagcagcggttccttacaccaatcggaacgtgcaggggtggggagctggccaatcaggcgcggagggcggggccgggcggggttccacctggcggctggctctcagtcccctcgctgtagtcgcggagctgtgtctgttcccaggagtccttcggcggctgttgtgtcgggagcctgatcgcgatggggacaaaggcgcaagtcgagaggaaactgttgtgcctcttcatattggcgatcctgttgtgctccctggcattgggcagtgttacagtgcactcttctgaacctgaagtcagaattcctgagaataatcctgtgaagagtcctgtgcctactcgggcttttcttctccccgtgtggagtggaagtttgaccaaggagacaccaccagactcgtttgctataataacaagatcacagcttcctatgaggaccgggtgaccttcttgccaactggtatcaccttcaagtccgtgacacgggaagacactgggacatacacttgtatggtctctgaggaaggcggcaacagctatggggaggtcaaggtcaagctcatcgtgcttgtgcctccatccaagcctacagttaacatcccctcctctgccaccattgggaaccgggcagtgctgacatgctcagaacaagatggttccccaccttctgaatacacctggttcttaagatgggatagtgatgcctacgaatcccaaaagcacccgtgccttcagcaactcttcctatgtcctgaatcccacaacaggagagctggtctttgatcccctgtcagcctctgatactggagaatacagctgtgaggcacggaatgggtatgggacacccatgacttcaaatgctgtgcgcatggaagctgtggagcggaatgtgggggtcatcgtggcagccgtccttgtttaccctgaactcctgggaatcttggtttttggcatctggtttgcctatagccgaggccactttgacagaacaaagaaagggacttcgagtaagaaggtgatttacagccagcctagtgcccgaagtgaaggagaattcaaacagacctcgtcattcctggtgtgagcctggtcggctcaccgcctatcatctgcatttgccttactcaggtgctaccggactctggcccctgatgtctgtagtttcacagaatgccttatttgtcttctacaccccacagggccccctacttcttcggatgtgtttttaataatgtcagctatgtgccccatcctccttcatgccctccctccctttcctaccactgctgagtggcctggaacttgtttaaagtgtttattccccatttctttgagggatcaggaaggaatcctgggtatgccattgacttcccttctaagtagacagcaaaaatggcgggggtcgcaggaatctgcactcaactgcccacctggctggcagggatctttgaataggtatcttgagcttggttctgggctctttccttgtgtactgacgaccagggccagctgttctagagcgggaattagaggctagagcggctgaaatggttgtttggtgatgacactggggtccttccatctctggggcccactctcttctgtcttcccatgggaagtgccactgggatccctctgccctgtcctcctgaatacaagctgactgacattgactgtgtctgtggaaaatgggagctcttgttgtggagagcatagtaaattttcagagaacttgaagccaaaaggatttaaaaccgctgctctaaagaaaagaaaactggaggctgggcgcagtggctcacgcctataatcccagaggctgaggcaggcggatcacctgaggtcaggagttcaagatcagcctgaccaacatggagaaaccctactaaaaatacaaagttagccaggcatagtggtgcatgcctgtaatcccagctgctcaggagcctggcaacaagagcaaaactccagctcaaaaaaaaaaagaaagaaaagaaagctggagctggtggcttaggccatcacccttcccttggctggaactactggacagacccttttgagatgtgcctgtggtgctgtggagatgtgtgtagtggtcttagctctttgttgagcttgtgtgtgtgttgtgtagtcttagagtatgctgaaattgggcgtgtgttggagggcttcttagctctttggtgagattgtatttctatgtgtttgtatcagctgaatgttgctggaaataaaaccttggtttgtcaaggctcttttttgtgggaagtaagtttggggaaaaggtctttgagggttcctaggctcctttgtacaacaggaaaatgcctcaaagcatgcttcccagcaacctggggctggttcccagtgcctggtcctgccccttcctggttcttatctcaaggcagagcttctgaatttcaggccttcattccagagccctcttgtggccaggccttcctttgctggaggaaggtacacagggtgaagctgatgctgtacttgggggatctccttggcctgttccaccaagtgagagaaggtacttactcttgtacctcctgttcagccaggtgcattaacagacctccctacagctgtaggaactactgtcccagagctgaggcaaggggatttctcaggtcatttggagaacaagtgctttagtagtagtttaaagtagtaactgctactgtatttagtggggtggaattcagaagaaatttgaagaccagatcatgggtggtctgcatgtgaatgaacaggaatgagccggacagcctggctgtcattgctttcttcctccccatttggacccttctctgcccttacatttttgtttctccatctaccaccatccaccagtctatttattaacttagcaagaggacaagtcaagggccctcttggcttgattttgcttctttctttctgtggaggatatactaagtgcgactttgccctatcctatttggaaatccctaacagaattgagttttctattaaggatccaaaaagaaaaacaaaatgctaatgaagccatcagtcaagggtcacatgccaataaacaataaattttccagaagaaatgaaatccaactagacaaataaagtagagcttatgaaatggttcagtaaagatgagtttgttgttttttgttttgttttgttttgtttttttaaagacggagtctcgctctgtcacccaggctggagtgcagtggtatgatcttggctcactgtaacctccgcctcccgggttcaagccattctcctgcctcagtctcctgagtagctgggattacgggtgcgtgccaccatgcctggctaatttttgtgtttttagtagagacagggtttcaccatgttggtcgggctggtctcaaactcctgacctcttgatccgcctgccttggcctcccaaagtgatgggattacagatgtgagccaccgtgccgagccaaggatgagatttttaaagtatgtttcttgttctgtgtcatggttggaagacagagtaggaaggatatggaaaaggtcatggggaagcagaggtgattcatggctctgtgaatttgaggtgaatggttccttattgtctaggccacttgtgaagaatatgagtcagttattcccagccttggaatttacttctagcttacaatggaccttttgaactggaaaacaccttgtctgcattcactttaaaatgtcaaaactaatttttataataaatgtttattttcacattgagtttgtttaaatcctgaagttcttaccttaagagaattgggactcctagagtgattggacattcaaaatattcctgatagtcttgttaattaagagattaggatatctttccattaccttgataattacgttttaatttagcttttttcattggcctgtgtttaaatgcaaataaccccacaatggacatttcctatgttaaagtgacatttaggggataaaaaatgagagcagttccatggattttggtgtttcccctgagacatgaactcagcataatctgggataaaatgattgagtgttaaggatgtgtttgttgttcctgtcgtttttttattttcttcaaagtatacaacatggtttgatatgcacatacatttgtgtaatgattgccatggtcaattaacacatcaccatttttgtgtgtgtgtgtgtgtgtgggtgtgagggagtcagctccgagccaggctggagtgcaatggtacaaccttggctcactgcaacctccacctcctgggttcaagcaattctcttgcctcagcctcctaagtagctgggactataggcgtgtgccaccatgcccagctaattttttgtatttttagtagagacggggtttcaccatgttggccaggatgatctcgatcccttgacctcatgatccgcccacctcggcctcccaaagtgctgggattacaggcgtgagtcactgcacccggccacatcacctcccatttttctatcttacgtattcagaacttgttcatcttgtaactgaaagcgtgtaccctttgaccaacactgtttttcctgtcttaacaggatctacagatcaaggacaggggaggggatagtggaggaaaacggagttagtcgtttctaaatgaggggacagtatgtttcttggggcctgaggacagcttaataaagtagacaaatgaagaaaaacaacaatttgcattaaaaaatatccaattcttta (SEQ ID NO: 658) Fynagagcatcagcaagagtagcagcgagcagcccgcgctggtggcggcggcgcgtcg NM_002037 NM_ttgcagttgcgccatctgtcaggagcggagccggcgaggagggggctgccgcggg 001122892cgaggaggaggggtcgccgcgagccgaaggccttcgagacccgcccgccgcccggcggcgagagtagaggcgaggttgttgtgcgagcggcgcgtcctctcccgcccgggcgcgccgcgcttctcccagcgcaccgaggaccgcccgggcgcacacaaagccgccgcccgcgccgcaccgcccggcggccgccgcccgcgccagggagggattcggccgccgggccggggacaccccggcgccgccccctcggtgctctcggaaggcccaccggctcccgggcccgccggggaccccccggagccgcctcggccgcgccggaggagggcggggagaggaccatgtgagtgggctccggagcctcagcgccgcgcagtttttttgaagaagcaggatgctgatctaaacgtggaaaaagaccagtcctgcctctgttgtagaagacatgtggtgtatataaagtttgtgatcgttggcggacattttggaatttagataatgggctgtgtgcaatgtaaggataaagaagcaacaaaactgacggaggagagggacggcagcctgaaccagttgctctgggtaccgctatggcacagaccccacccctcagcactaccccagcttcggtgtgacctccatccccaactacaacaacttccacgcagccgggggccaaggactcaccgtctttggttggtgtgaactcttcgtctcatacggggaccttgcgtacgagaggaggaacaggagtgacactctttgtggccctttatgactatgaagcacggacagaagatgacctgagttttcacaaaggagaaaaatttcaaatattgaacagctcggaaggagattggtgggaagcccgctccttgacaactggagagacaggttacattcccagcaattatgtggctccagttgactctatccaggcagaagagtggtactttggaaaacttggccgaaaagatgctgagcgacagctattgtcctttggaaacccaagaggtacctttcttatccgcgagagtgaaaccaccaaaggtgcctattcactttctatccgtgattgggatgatatgaaaggagaccatgtcaaacattataaaattcgcaaacttgacaatggtggatactacattaccacccgggcccagtttgaaacacttcagcagcttgtacaacattactcagagagagctgcaggtctctgctgccgcctagtagttccctgtcacaaagggatgccaaggcttaccgatctgtctgtcaaaaccaaagatgtctgggaaatccctcgagaatccctgcagttgatcaagagactgggaaatgggcagtttggggaagtatggatgggtacctggaatggaaacacaaaagtagccataaagactcttaaaccaggcacaatgtcccccgaatcattccttgaggaagcgcagatcatgaagaagctgaagcacgacaagctggtccagctctatgcagtggtgtctgaggagcccatctacatcgtcaccgagtatatgaacaaaggaagtttactggatttcttaaaagatggagaaggaagagctctgaaattaccaaatcttgtggacatggcagcacaggtggctgcaggaatggcttacatcgagcgcatgaattatatccatagagatctgcgatcagcaaacattctagtggggaatggactcatatgcaagattgctgacttcggattggcccgattgatagaagacaatgagtacacagcaagacaaggtgcaaagttccccatcaagtggacggcccccgaggcagccctgttgcgggaggttcacaatcaagtctgacgtgtggtcttttggaatcttactcacagagctggtcaccaaaggaagagtgccatacccaggcatgaacaaccgggaggtgctggagcaggtggagcgaggctacaggatgccctgcccgcaggactgccccatctctctgcatgagctcatgatccactgctggaaaaaggaccctgaagaacgccccacttttgagtacttgcagagcttcctggaagactactttaccgcgacagagccccagtaccaacctggtgaaaacctgtaaggcccgggtctgcggagagaggccttgtcccagaggctgccccacccctccccattagctttcaattccgtagccagctgctccccagcagcggaaccgcccaggatcagattgcatgtgactctgaagctgacgaacttccatggccctcattaatgacacttgtccccaaatccgaacctcctctgtgaagcattcgagacagaaccttgttatttctcagactttggaaaatgcattgtatcgatgttatgtaaaaggccaaacctctgttcagtgtaaatagttactccagtgccaacaatcctagtgctttccttttttaaaaatgcaaatcctatgtgattttaactctgtcttcacctgattcaactaaaaaaaaaaaagtattattttccaaattgtggcctctttgtctaaaacaatttaaattttttttcatgttttaacaaaaaccaatcaggacaggtgtttgtttttgttttcttttttataaatatgaatatatataatattttatgtccctgtacatatacaatgtgggtgctaatgtggagactgtggccggcctgagccaccaagctgcgggacccagagggaggattttactgcaagtcagcatcaaagcaccggtgttattctgaaaacaccagtggcctcatttttggcttttgcaaagcatgaattttttcatttggattgatctttcctggttcatgactgtacctgtaggtggttgttactttgactcttttcaggaaccaccccccaagctgaatttacaagttctgttagcactatttgcttcaacttactgcgatttgttctcaaaacttaaaaataagcaagcaaatggctgatactaccaagagaactggaagatggataccacacaaacttcttgtataaaaatatgaatgctgaaatgtttcagacatttttaatttaataaacctgtaaccacatttaagtgatctttaaacccatagcattgtttgtcatggcaacccgctttaactttctcatgcaactaaaatttctgggggaaatgagggtgggggttgtacatttcccattgtaaaataagtgttttaaatgtcctgtactgctaacgaatgactttctatatgtccaggagttctccagtggaataactatgcactactttacatttcatggggatgcacaaaaacaaaaaagtattacatttttagttgctgtttgtaccaaccttaaattacatatgtttaacaacaacaaatcaaaaatcctatactattgagtttttaatactgactagcaactctgaagtcttaattccttttttgttatgatttatttgtgagtttacatttttaaattgtttaactttcttaatttagtaattaaaaagagagcattttacatttgaa (SEQ ID NO: 659) Ypel2gccgcggcggtggcggagactgtggctttaagagcgtgccgggagcccgagccc NM_ NN_cagccgggccgcgcttcgccgctgcgcaccccagcggagccaagccccacgctg 001005404001005341 gccggacagggccgcctgtcgccgggctgctgagaactagccctagacctctgcgtgagggttcttctgccgaagacatcaccagtgtgtggagcctgccacacccacccgctgccaaaccacggcctttacctgtgtcttccggtgtttcccgtgcgacccatcctgtgggagtgcctcgtgggctgccccagagttcaccccacactcagcagcaccaatggtgaagatgacaagatcgaagactttccaggcatatctgccctcctgccaccggacctacagctgcattcactgcagagctcacttggccaatcatgatgaacttttttttccaagtcattccaaggaagtcaaggacgagcatacctctttaactcagtagttaatgtgggctgtgggcctgcagaagagcgagtgttgctttacaggactgcatgcagtcgcagacatttactgtgaaaactgcaaaaccactctgggctggaaatacgaacatgcttttgaaagcagccagaaatataaagaaggcaaatacatcattgaactagcacacatgatcaaggacaatggctgggactgattggacagcatctttcccaacccagtgtccacgtgaacgccattcaaccgaacattcttcccaagcgtgagagagtgactgacacttggttccatccatttaggggccttgccatccggggcatcctcccaccctgacgccatctttctggtgaccggcctctaaatcgctgtctctctgtctctttgctttgtatctgtttgtgagttgatcctggcttctctctctgttctagttttggctgaaaacaaaacaacaaaaggaacagatccttgaccgcatggcggcagcccaccttggtaagggccccagggcccatgcgagagctgcctgatggcctcttgtcaggagagcagtggcacgggggcgtgaggaagagggaaaggggaaactctaagggtcctggcgcggggaaggggtggaagggtggaggtaggaacaaaattgcgccgctcctggagacctgataacttaggcttgaaataattgacttgtctaaaaggacaaagagaaaaaaaaaatacctcatgactgcattctactgactagaagcttctgttcctgacaccaaatgtgccaggttagcaaatgagcacaagatgtggccctgattctagttggtggggcaagggcctggttctcctgggctgagtgggggagtgtcctggcagcagcgagtgacctgggcagtggccaggtgggtgcgatgactctgatgcctcactcagtctctgggcaatcatcatctttgcctctagccaccgtagataaggtgtgaagggactgctgtttgcaatgggcttaccatccaaatatcccaaaggctttgaccagcaaccaagtaaaatcagtaattgaggagagcagggcacaaaggggctgcagtttgggagctcctgaagaaatggctcagatattgagtcagagaaataaaaagtaggatcagttagcaattctaactgcccttccttctgacccctcataagaggagtgtggtgagggaggggactgggtaggggtcatcccaggaggaggggtttacattggaaccagttcaggttcggtgcatctttcctcttcggttttacagtggcttccgtgggatcgtcaatttcttgttcttagagtttcgggtgtttttctccagtcttgttactgtagactgtagaaagcacgggccccaggctctgagcttagtaataacctggctggtagattcctcatgcccctaattgtcccacttaggcctgaatgtcttgcatggagagaaatctcctgtcagtgtggtccagcagcagggaggagttctgcccaaattccgatatcaccccttcccccatccaagcatccttcgattagggaagtggagagcacatccctgtaaggcccataagagaaagaggagtttgttacatttaatcaacactgtgaagtctgttctacagcaattcagccattacacagtatatgactgaaactcatttaactgggttaatttcatttcttagactgaatatattattgttaagatacgtgtgcgtgttaggtaattctcagcatctcctccaagtaggccgaccttctcggaaaattcaccctaaaagtctcacaaaagaatgagttcatggggagattctgtaaagtgatgaactgagatgaaagcagccaacagcccaggagcttttcagaatagcgtctgcagcagaaccagtttccattcagagcgcgtccttggtggaaatgcttttttgtgtgtctccacgcgctgatggtggaatgggagccccaagacgtgtgggcttagaaatcaacttttgttccccaaggcttcttgtccagatctttccagtgctttcatagccctgggagatcaagttgttctccccactttactgcaaggtagactgaagttcagaagaaatactgaatttctgctcccagaagaatagtttctctggctcacaggcccaagttctcaatgaaatcgttttttaactttcacattcctaagctggcttcccggcacagaagccatggatttcccctctctcccttccccctcctcaaggaaatagtcttcctttatggattttcattggactctttcacagcgattgtcctggctgtttattgatagtccttcccataagaaaatggggttaaacatggggtaggtattttgtctttcaaactacaaatggaatgtggtgacataaactagacatggggtgccctcaagttttccaaggggaccaatgtgccactgttcttccttggggatgaggcctttgactgttggatggatcagagcaggctccagtcagaccctggttctgaatgttttttttttcggtgactatccagtgagccttcagtgggtgcaaggcgccatacttgctgtgagagagctgagtagagtgttggtttttccataattacagggggaaaaaaagtcattaggctttccctttgtgtcagtgaaaccaaaagtgcttcttacaacgttcgctctgttcatgggttgtctatctaacattgagcagcattggagaggccacagctgagctatggagatgctaaattaactcatggcctcagtcagttcattcttaatttcctcaccaaattattgacttagagcataaccaaagacctcattcattcaccccaggtgggttggggtaattggagtttgttggtgaagtttgggggcggggtgttgggagtagagacagggtaaggggacgtgagaaaggaaaaggcatgaagttctatacctcagccagcagctgccttcgtttggaactgaagtccagccagcagactctctagctccatctcccctgtgccaccctaggtcatatgaccttggccaccttggagtagacccagacccctcgggacccgggacattagtctcaggctgctgatggattgatttgacatgaaccaaacacagccaaactcgatacccacaagctgtcagctgaacctgactgagtgttcttcctgagttcacgaggataggctagagtgcatttttactggtggatcagtgtgtgcgaaagagatgaccctttataaagagattttcaagtggatatatataaaagaaacagttgcttgtaaaatatacttttgtaaataatatttaattttttaaataatatatttggtgctgttttctcagatcccctgagagcactttttattttccttttaaattctatggtttcctttgcatttcttgaagtatattttaagggaaacagtgatcaccaatacatgttttcagttttttttttttttaaggtctctatcactttaatctggatcaaggctttgaagcaatgcctctctgcattttttccccagtggaacagactctgcagtacattaatcaggttgagaattgaaatattttcttgcatcagtattggctagaaaagaaaataaataaaaccaagttaatttagtagtaacaacttacagtgattcttcctgttggaagaatttccaacaaatcagaatcacgtttttagttgtgcgtgtgcgcgcacacgtgtgtaaaaagcactttcgattgtgcctcctgttttctcgagtggggacactttaactacagtttacacctcgggcgcataaagtttttcttctctttctctctggttgtttctgtttctgagtggaccaacagcagaacccacgaggatttgttttgagtatggagctgttgcgggtttgctcctttttcttgctttgcgtgctcagtttttacagactgtaaaggagatgtgttgtttgtgaagatggagcagagtcaaatctgtgcttctaactgagatgagagtgtattaatcacgtatcgcagggctccagctgttttagaagccacatcatgttaaacattaactggtttggattaaaagaacattaatattataatacacatatcttagtggtaaacagctttttttttttaaggtcagattgcctcaggtttagaaagaggctgagaaatcaaatcttgaacacaatcaacttacatattttaaaggaatctgcctcaaatgagaaaatatgctagttatctagatagaggaaagagatatttacttttttaaaaattaaaatagttatgaaatctggcagaaaaggtaaagcctagaagaaactatgaaagctattctcatgttaccaaattctatctgcgcattttgtttttgtataacatttcggtgacagtgggagtcggttccctttcccaacctgcagagactatcttccaatacagaatctgtcttttttatgcttgtgtttacaaactgtatttgttgggtttgggtttttgtttctttggtggcaatttcaggtcactttgcttctataacaaaggtaattgttttcattataatttgtcttcacctatcctgtatttgtacatagtgattcagtattagagaaaagtgcaagtttctgtcatatttccaatagtgttggtgctcatttgagaaaataaaagttttcaaatattaactcttaaaaaaaaaa (SEQ ID NO: 660) Pkd1ccctcccctcccgatcctcatccccttgccctcccccagcccagggacttttccggaa NM_002742NM_008858 agtttttattttccgtctgggctctcggagaaagaagctcctggctcagcggctgcaaaactttcctgctgccgcgccgccagcccccgccctccgctgcccggccctgcgccccgccgagcgatgagcgcccctccggtcctgcggccgcccagtccgctgctgcccgtggcggcggcagctgccgcagcggccgccgcactggtcccagggtccgggcccgggcccgcgccgttcttggctcctgtcgcggccccggtcgggggcatctcgttccatctgcagatcggcctgagccgtgagccggtgctgctgctgcaggactcgtccggggactacagcctggcgcacgtccgcgagatggcttgctccattgtcgaccagaagttccctgaatgtggtttctacggaatgtatgataagatcctgctttttcgccatgaccctacctctgaaaacatccttcagctggtgaaagcggccagtgatatccaggaaggcgatcttattgaagtggtcttgtcagcttccgccacctttgaagactttcagattcgtccccacgctctctttgttcattcatacagagctccagctttctgtgatcactgtggagaaatgctgtgggggctggtacgtcaaggtcttaaatgtgaagggtgtggtctgaattaccataagagatgtgcatttttaaatacccaacaattgcagcggtgtgaggcggagaaggctctcaaacgtttccctcactggggtcagcaccatccgcacatcatctgctgaactctctacaagtgcccctgatgagccccttctgcaaaaatcaccatcagagtcgtttattggtcgagagaagaggtcaaattctcaatcatacattggacgaccaattcaccttgacaagattttgatgtctaaagttaaagtgccgcacacatttgtcatccactcctacttcccggcccacagtgtgccagtactgcaagaagcttctgaaggggcttttcaggcagggcttgcagtgcttaagattgcagattatactgccataaacgttgtgcaccgaaagtaccaaacaactgccttggcgaagtgaccattaatggagatttgcttagccctggggcagagtctgatgtggtcatggaagaagggagtgatgacaatgatagtgaaaggaacagtgggctcatggatgatatggaagaagcaatggtccaagatgcagagatggcaatggcagagtgccagaacgacagtggcgagatgcaagattcagacccagaccacgaggacgccaacagaaccatcagtccatcaacaagcaacaatatcccactcatgagggtagtgcagtctgtcaaacacacgaagaggaaaagcagcacagtcatgaaagaagaatggatggtccactacaccagcaaggacacgctgcggaaacggcactattggagattggatagcaaatgtattaccctctttcagaatgacacaggaagcaggtactacaaggaaattcctttatctgaaattttgtctctggaaccagtaaaaacttcagctttaattcctaatggggccaatcctcattgtttcgaaatcactacggcaaatgtagtgtattatgtgggagaaaatgtggtcaatccttccagcccatcaccaaataacagtgttctcaccagtggcgttggtgcagatgtggccaggatgtgggagatagccatccagcatgcccttatgcccgtcattcccaagggctcctccgtgggtacaggaaccaacttgcacagagatatctctgtgagtatttcagtatcaaattgccagattcaagaaaatgtggacatcagcacagtatatcagatttttcctgatgaagtactgggttctggacagtttggaattgtttatggaggaaaacatcgtaaaacaggaagagatgtagctattaaaatcattgacaaattacgatttccaacaaaacaagaaagccagcttcgtaatgaggttgcaattctacagaaccttcatcaccctggtgttgtaaatttggagtgtatgtttgagacgcctgaaagagtgtttgttgttatggaaaaactccatggagacatgctggaaatgatcttgtcaagtgaaaagggcaggttgccagagcacataacgaagtttttaattactcagatactcgtggctttgcggcaccttcattttaaaaatatcgttcactgtgacctcaaaccagaaaatgtgttgctagcctcagctgatccttttcctcaggtgaaactttgtgattttggttttgcccggatcattggagagaagtctttccggaggtcagtggtgggtacccccgcttacctggctcctgaggtcctaaggaacaagggctacaatcgctctctagacatgtggtctgttggggtcatcatctatgtaagcctaagcggcacattcccatttaatgaagatgaagacatacacgaccaaattcagaatgcagctttcatgtatccaccaaatccctggaaggaaatatctcatgaagccattgatcttatcaacaatttgccgcaagtaaaaatgagaaagcgctacagtgtggataagaccttgagccacccttggctacaggactatcagacctggttagatttgcgagagctggaatgcaaaatcggggagcgctacatcaccctttgaaagtgtttgacctgaggtgggagaagtatgcaggcgagcaggggagcagtaccccacacacctgatcaatccaagtgctagccacagtgacactcctgagactgaagaaacagaaatgaaagccctcggtgagcgtgtcagcatcctctgagttccatctcctataatctgtcaaaacactgtggaactaataaatacatacggtcaggtttaacatttgccttgcagaactgccattattttctgtcagatgagaacaaagctgttaaactgttagcactgttgatgtatctgagttgccaagacaaatcaacagaagcatttgtattttgtgtgaccaactgtgttgtattttttcaaaagttccctgaaacacgaaacttgttattgtgaatgattcatgttatatttaatgcattaaacctgtctccactgtgcctttgcaaatcagtgtttttcttactggagcttcattttggtaagagacagaatgtatctgtgaagtagttctgtttggtgtgtcccattggtgagtcattgtaaacaaactcttgaagagtcgattatttccagtgttctatgaacaactccaaaacccatgtgggaaaaaaatgaatgaggagggtagggaatattaatcctaagacacttttatgcatgattcaagttttaatgtatagttttgatttcctttgcctgcctggtgtgcctcagttttatttaaactcaagacaatgcacctagctgtgcaagacctagtgctcttaagcctaaatgccttagaaatgtaaactgccatatataacagatacatttccctctttcttataatactctgttgtactatggaaaatcagctgctcagcaacctttcacctttgtgtatttttcaataataaaaaatattcttgtcaaaa (SEQ ID NO: 661) Ptpn2gctcgggcgccgagtctgcgcgctgacgtccgacgctccaggtactttccccacgg NM_002828NM_008977 ccgacagggcttggcgtgggggcggggcgcggcgcgcagcgcgcatgcgccgcagcgccagcgctctccccggatcgtgcggggcctgagcctctccgccggcgcaggctctgctcgcgccagctcgctcccgcagccatgcccaccaccatcgagcgggagttcgaagagttggatactcagcgtcgctggcagccgctgtacttggaaattcgaaatgagtcccatgactatcctcatagagtggccaagtttccagaaaacagaaatcgaaacagatacagagatgtaagcccatatgatcacagtcgtgttaaactgcaaaatgctgagaatgattatattaatgccagtttagttgacatagaagaggcacaaaggagttacatcttaacacagggtccacttcctaacacatgctgccatttctggcttatggtttggcagcagaagaccaaagcagttgtcatgctgaaccgcattgtggagaaagaatcggttaaatgtgcacagtactggccaacagatgaccaagagatgctgtttaaagaaacaggattcagtgtgaagctcttgtcagaagatgtgaagtcgtattatacagtttcatctactacaattagaattatatcaatagtggtgaaaccagaacaatatctcactttcattatactacctggccagattttggagtccctgaatcaccagcttcatttctcaatttcttgtttaaagtgagagaatctggctccttgaaccctgaccatgggcctgcggtgatccactgtagtgcaggcattgggcgctctggcaccttctctctggtagaatcttgtcttgttttgatggaaaaaggagatgatataacataaaacaagtgttactgaacatgagaaaataccgttatgggtcttattcagaccccagatcaactgagattctcatacatggctataatagaaggagcaaatttgtataaagggagattctagtatacagaaacgatggaaagaactttctaaggaagacttatctcctgcctttgatcattcaccaaacaaaataatgactgaaaaagacaatgggaacagaataggtctagaagaagaaaaactgacaggtgaccgatgtacaggactttcctctttaaatgcaagatttcaatggaggagaacagtgagagtgctctacggaaacgtattcgagaggacagaaaggccaccacagctcagaaggtgcagcagatgaaacagaggctaaatgagaatgaacgaaaaagaaaaaggtggttatattggcaacctattctcactaagatggggtttatgtcagtcattttggttggcgcttagttggctggacactgttttttcagcaaaatgccctataaacaattaattttgcccagcaagcttctgcactagtaactgacagtgctacattaatcataggggtttgtctgcagcaaacgcctcatatcccaaaaacggtgcagtagaatagacatcaaccagataagtgatatttacagtcacaagcccaacatctcaggactcttgactgcaggttcctctgaaccccaaactgtaaatggctgtctaaaataaagacattcatgtttgttaaaaactggtaaattttgcaactgtattcatacatgtcaaacacagtatttcacctgaccaacattgagatatcctttatcacaggatttgtttttggaggctatctggattttaacctgcacttgatataagcaataaatattgtggttttatctacgttattggaaagaaaatgacatttaaataatgtgtgtaatgtataatgtactattgacatgggcatcaacacttttattcttaagcatttcagggtaaatatattttataagtatctatttaatcttttgtagttaactgtacatttaagagctcaatttgaaaaatctgttactaaaaaaataaattgtatgtcgattgaattgtactggatacattttccatttttctaaagagaagtttgatatgagcagttagaagttggaataagcaatttctactatatttttgcatttcttttatgttttacagttttccccattttaaaaagaaaagcaaacaaagaaacaaaagtttttcctaaaaatatctttgaaggaaaattctccttactgggatagtcaggtaaacagttggtcaagactttgtaaagaaattggtttctgtaaatcccattattgatatgtttatttttcatgaaaatttcaatgtagttggggtagattatgatttaggaagcaaaagtaagaagcagcattttatgattcataatttcagtttactagactgaagttttgaagtaaacacttttcagtttctttctacttcaataaatagtatgattatatgcaaaccttacattgtcattttaacttaatgaatattttttaaagcaaactgtttaatgaatttaactgctcatttgaatgctagctttcctcagatttcaacattccattcagtgtttaatttgtcttacttaaacttgaaattgttgttacaaatttaattgctaggaggcatggatagcatacattattatggatagcataccttatttcagtggttttcaaactatgctcattggatgtccaggtgggtcaagaggttactttcaaccacagcatctctgccttgtctctttatatgccacataagatttctgcataaggcttaagtattttaaagggggcagttatcatttttaaaacagtttggtcgggcgcggtggctcatgcctgtaatcccagcactttgggaggctgaagtgggcagatcacctgaggtcaggagttcaagaccagcctggccaacgtggtgaaacaccatctctactaaaaatgcaaaaattagctgggcatggtggagggcacctgtaatctcagctactcaggaggctgaggtaggagaattgcttgaacccaggagatggaggttgcagtgagctgagatcacgtcactgcactccagccagggcgacagagcgagactccatctcaaaagaaacaaacaaaaaaaacagtttgggccgggtgtggtggctcacgcttgtaatcccagcacttcggaaggccaaggcgggcggatcacgaggtcaagagatggagactgtcctggccaacatggtgaaatcccttctttactaaaaatacaaaaattatctgggcgtggtggtgcatgccggtagtcccagctccttgggttggctaaggcaggagaatcacttgaacccgggaggcagaggttgcagtgagccgagattgcaccactgcactccagcctggcaacagagcaagacttcgtctc (SEQ ID NO: 662) Grk6cggctggctgcggcggccggggaggcggggaggccgcggcgcggtcactgcg NM__ NM_agccgagccgagccgcgccgagccgcgccgatcgccatccggcctcggcactcg 001004106001038018 cgcgcgatcccggccggcggcgcggcccggcgggccaggcggcgccacagcccatggagctcgagaacatcgtagcgaacacggtgctactcaaggcccgggaaggtggcggtggaaatcgcaaaggcaaaagcaagaaatggcggcagatgctccagttccctcacatcagccagtgcgaagagctgcggctcagcctcgagcgtgactatcacagcctgtgcgagcggcagcccattgggcgcctgctgttccgagagttctgtgccacgaggccggagctgagccgctgcgtcgccttcctggatggggtggccgagtatgaagtgaccccggatgacaagcggaaggcatgtgggcggcagctaacgcagaattttctgagccacacgggtcctgacctcatccctgaggtcccccggcagctggtgacgaactgcacccagcggctggagcagggtccctgcaaagaccttttccaggaactcacccggctgacccacgagtacctgagcgtggccccttttgccgactacctcgacagcatctacttcaaccgtttcctgcagtggaagtggctggaaaggcagccagtgaccttaaaacaccttcaggcaataccgagtcctgggcaaaggtggctttggggaggtgtgcgcctgccaggtgcgggccacaggtaagatgtatgcctgcaagaagctagagaaaaagcggatcaagaagcggaaaggggaggccatggcgctgaacgagaagcagatcctggagaaagtgaacagtaggtttgtagtgagcttggcctacgcctatgagaccaaggacgcgctgtgcctggtgctgacactgatgaacgggggcgacctcaagttccacatctaccacatgggccaggctggcttccccgaagcgcgggccgtcttctacgccgccgagatctgctgtggcctggaggacctgcaccgggagcgcatcgtgtacagggacctgaagcccgagaacatcttgctggatgaccacggccacatccgcatctctgacctgggactagctgtgcatgtgcccgagggccagaccatcaaagggcgtgtgggcaccgtgggttacatggctccggaggtggtgaagaatgaacggtacacgttcagccctgactggtgggcgctcggctgcctcctgtacgagatgatcgcaggccagtcgcccttccagcagaggaagaagaagatcaagcgggaggaggtggagcggctggtgaaggaggtccccgaggagtattccgagcgcttttccccgcaggcccgctcactttgctcacagctcctctgcaaggaccctgccgaacgcctggggtgtcgtgggggcagtgcccgcgaggtgaaggagcaccccctctttaagaagctgaacttcaagcggctgggagctggcatgctggagccgccgttcaagcctgacccccaggccattttactgcaaggatgttctggacattgaacagttctctacggtcaagggcgtggagctggagcctaccgaccaggacttctaccagaagtttgccacaggcagtgtgcccatcccctggcagaacgagatggtggagaccgagtgcttccaagagctgaatgtctttgggctggatggctcagttcccccagacctggactggaagggccagccacctgcacctcctaaaaagggactgctgcagagactcttcagtcgccaagattgctgtggaaactgcagcgacagcgaggaagagctccccacccgcctctagcccccagcccgaggcccccaccagcagttggcggtagcagctactccgagcgccgtttacagttttgcacagtgatcttccccattgtccactcaagtcgtggcctggggaacacagacggagctgtccccagtgtcctccgtccctcagcccctggcctggctgagtttggcagggcctgggccatccctgggacaaaggtgcgtcccttcagctcttctccgtggagctcggggctttctgtatttatgtatttgtacgaatgtatatagcgaccagagcattcttaattcccgccgcagacctggcgcccccgccttggctcctgggggcagccagccctggctgggagagcgggagctggcagaggagccactgccaaactcaaggctcctctggcccagcttggatggctgagggtggtcacacccctgagccttcagcactgtgctggccaccccggcctctgagtaagactcgtgcctccccctgctgccctgggctcaggctgctaccctctggggcccaaagctgtcccttctcagtgcttgtcagcgctgggtctggggcctctgtatgccctaggcctgtgccaaagtggccagagattgggctgcctgtgatacccatcagcccactgccccggccggcccagaaggtctgcctctgccttccagctcccacagcctggtccctgatactgggctctgtcctgcagacacctctttcagaaacgcccaagcccagcccctaggagggggtggggcatccctggtcaaccctcaaacattccggactcccctcataacaatagacacatgtgcccagcaataatccgccccttcctgtgtgcgcctgtggggtgcgtgcgcgcgcgtgtgtacctgtgtgggtgaaggggatagggcgaggctgtgcctgtgccccaggtcccagccctggcccttcccagactgtgatggccatcctggtcccagtgttagggtagcatgggattacagggccctgttttttccatatttaaagccaatttttattactcgttttgtccaacgtaa (SEQ ID NO: 663) Cdkn2acgagggctgcttccggctggtgcccccgggggagacccaacctggggcgacttca NM_000077 NM_ggggtgccacattcgctaagtgctcggagttaatagcacctcaccgagcactcgctc 001040654acggcgtccccttgcctggaaagataccgcggtccctccagaggatttgagggacagggtcggagggggctcttccgccagcaccggaggaagaatgaggaggggctggctggtcaccagagggtggggcggaccgcgtgcgctcggcggctgcggagagggggagagcaggcagcgggcggcggggagcagcatggagccggcggcggggagcagcatggagccttcggctgactggctggccacggccgcggcccggggtcgggtagaggaggtgcgggcgctgctggaggcgggggcgctgcccaacgcaccgaatagttacggtcggaggccgatccaggtcatgatgatgggcagcgcccgagtggcggagctgctgctgctccacggcgcggagcccaactgcgccgaccccgccactctcacccgacccgtgcacgacgctgcccgggagggcttcctggacacgctggtggtgctgcaccgggccggggcgcggctggacgtgcgcgatgcctggggccgtctgcccgtggacctggctgaggagctgggccatcgcgatgtcgcacggtacctgcgcgcggctgcggggggcaccagaggcagtaaccatgcccgcatagatgccgcggaaggtccctcagacatccccgattgaaagaaccagagaggctctgagaaacctcgggaaacttagatcatcagtcaccgaaggtcctacagggccacaactgcccccgccacaacccaccccgctttcgtagttttcatttagaaaatagagcttttaaaaatgtcctgccttttaacgtagatatatgccttcccccactaccgtaaatgtccatttatatcattttttatatattcttataaaaatgtaaaaaagaaaaacaccgcttctgccttttcactgtgttggagttttctggagtgagcactcacgccctaagcgcacattcatgtgggcatttcttgcgagcctcgcagcctccggaagctgtcgacttcatgacaagcattttgtgaactagggaagctcaggggggttactggcttctcttgagtcacactgctagcaaatggcagaaccaaagctcaaataaaaataaaataattttcattcattcactcaaaaaaaaaaaaaa (SEQ ID NO: 664) Sbf1gggcgggccggctggctgggaagatggcggcgggaacctgggccgccgccgcc NM_002972 NM_gccgccgccgccgccgcggagcgaaccaggggtgtccggggtgcgcggtccag 001170561ggccggggccgggccatgagcgcgccgtcctcgagtccccgagccgcggagcccgcccgcgcccctcgggccgccccgcgtccctcgccatggcgcggctcgcggactacttcgtgctggtggcgttcgggccgcacccgcgcgggagtggggaaggccagggccagattctgcagcgcttcccagagaaggactgggaggacaacccattcccccagggcatcgagctgttttgccagcccagcgggtggcagctgtgtcccgagaggaatccaccgaccttctttgttgctgtcctcaccgacatcaactccgagcgccactactgcgcctgcttgaccttctgggagccagcggagccttcacaggaaacgacgcgcgtggaggatgccacagagagggaggaagagggggatgagggaggccagacccacctgtctcccacagcacctgccccatctgcccagctgtttgcaccgaagacgctggtactggtgtcgcgactcgaccacacggaggtgttcaggaacagccttggcctcatctatgccatccacgtggagggcctgaatgtgtgcctggagaacgtgattgggaacctgctgacgtgcactgtgcccctggctgggggctcgcagaggacgatctctttgggggctggtgaccggcaggtcatccagactccactggccgactcgctgcccgtcagccgctgcagcgtggccctgctcttccgccagctaggcatcaccaacgtgctgtctttgttctgtgccgccctcacggagcacaaggttctcttcctgtcccggagctaccagcggctcgccgatgcctgtaggggcctcctggcactgctgtttcctctcagatacagcttcacctatgtgcccatcctgccggctcagctgctggaggtcctcagcacacccacgcccttcatcattggggtcaacgcggccttccaggcagagacccaggagctgctcgatgtgattgttgctgatctggatggagggacggtcaccattcctgagtgtgtgcacattccacccttgccagagccactgcagagtcagacgcacagtgtgctgagcatggtcctggacccggagctggagttggctgacctcgccttccctccgcccacgacatccacctcctccctgaagatgcaggacaaggagctgcgcgcggtcttcctgcggctgttcgctcagctgctgcagggctatcgctggtgcctgcacgtcgtgcgcatccacccggagcctgtcatccgcttccataaggcagccttcctgggccagcgtgggctggtagaggacgatttcctgatgaaggtgctggagggcatggcctttgctggctttgtgtcagagcgtggggtcccataccgccctacggacctgttcgatgagctggtggcccacgaggtggcaaggatgcgggcggatgagaaccacccccagcgtgtcctgcgtcacgtccagaaactggcagagcagctctacaagaacgagaacccgtacccagccgtggcgatgcacaaggtacagaggcccggtgagagcagccacctgcgacgggtgccccgacccttcccccggctggatgagggcaccgtgcagtggatcgtggaccaggctgcagccaagatgcagggtgcacccccagctgtgaaggccgagaggaggaccaccgtgccctcagggccccccatgactgccatactggagcggtgcagtgggctgcatgtcaacagcgcccggcggctggaggttgtgcgcaactgcatctcctacgtgtttgaggggaaaatgcttgaggccttagaagctgctcccagccgtgttgagggccctgaaggggcgagctgcccgccgctgcctcgcccaggagctgcacctgcatgtgcagcagaaccgtgcggtcctggaccaccagcagtttgactttgtcgtccgtatgatgaactgctgcctgcaggactgcacttctctggacgagcatggcattgcggcggctctgctgcctctggtcacagccttctgccggaagctgagcccgggggtgacgcagtttgcatacagctgtgtgcaggagcacgtggtgtggagcacgccacagttctgggaggccatgttctatggggatgtgcagactcacatccgggccctctacctggagcccacggaggacctggcccccgcccaggaggttggggaggcaccttcccaggaggacgagcgctctgccctagacgtggcttctgagcagcggcgcttgtggccaactctgagtcgtgagaagcagcaggagctggtgcagaaggaggagagcacggtgttcagccaggccatccactatgccaaccgcatgagctacctcctcctgcccctggacagcagcaagagccgcctacttcgggagcgtgccgggctgggcgacctggagagcgccagcaacagcctgggcaccaacagcatggctggcagtgtggccgagagctatgacacggagagcggcttcgaggatgcagagacctgcgacgtagctggggctgtggtccgcttcatcaaccgctttgtggacaaggtctgcacggagagtggggtcaccagcgaccacctcaaggggagcatgtcatggtgccagacattgtccagatgcacatcgagaccctggaggccgtgcagcgggagagccggaggctgccgcccatccagaagcccaagctgctgcggccgcgcctgctgccgggtgaggagtgtgtgctggacggcctgcgcgtctacctgctgccggatgggcgtgaggagggcgcggggggcagtgctgggggaccagcattgctcccagctgagggcgccgtcttcctcaccacgtaccgggtcatcttcacggggatgcccacggaccccctggttggggagcaggtggtggtccgctcatcccggtggctgcgctgaccaaggagaagcgcatcagcgtccagacccctgtggaccagctcctgcaggacgggctccagctgcgctcctgcacattccagctgctgaaaatggcctttgacgaggaggtggggtctgacagcgccgagctcttccgtaagcagctgcataagctgcggtacccgccggacatcagggccacctttgcgttcaccttgggctctgcccacacacctggccggccaccgcgagtcaccaaggacaagggtccttccctcagaaccctgtcccggaacctggtcaagaacgccaagaagaccatcgggcggcagcatgtcactcgcaagaagtacaacccccccagctgggagcaccggggccagccgccccctgaggaccaggaggacgagatctcagtgtcggaggagctggagcccagcacgctgaccccgtcctcagccctgaagccctccgaccgcatgaccatgagcagcctggtggaaagggcttgctgtcgcgactaccagcgcctcggtctgggcaccctgagcagcagcctgagccgggccaagtctgagcccttccgcatttctccggtcaaccgcatgtatgccatctgccgcagctacccagggctgctgatcgtgccccagagtgtccaggacaacgccctgctgcgcgtgtcccgctgctaccgccagaaccgcttccccgtggtctgctggcgcagcgggcggtccaaggcggtgctgctgcgctctggaggcctgcatggcaaaggtgtcgtcggcctcttcaaggcccagaacgcaccttctccaggccagtcccaggcggactcgagtagcctggagcaggagaagtacctgcaggctgtggtcagctccatgccccgctacgccgacgcgtcgggacgcaacacgcttagcggcttctcctcagcccacatgggcagtcacgttcccagccccagagccagggtcaccacgctgtccaaccccatggcggcctcggcctccagacggaccgcaccccgaggtaagtggggcagtgtccggaccagtggacgcagcagtggccttggcaccgatgtgggctcccggctagctggcagagacgcgctggccccaccccaggccaacgggggccctcccgacccgggcttcctgcgtccgcagcgagcagccctctatatccttggggacaaagcccagctcaagggtgtgcggtcagaccccctgcagcagtgggagctggtgcccattgaggtattcgaggcacggcaggtgaaggctagcttcaagaagcggctgaaagcatgtgtcccaggctgccccgctgctgagcccagcccagcctccttcctgcgctcactggaggactcagagtggctgatccagatccacaagctgctgcaggtgtctgtgctggtggtggagctcctggattcaggctcctccgtgctggtgggcctggaggatggctgggacatcaccacccaggtggtatccttggtgcagctgctctcagaccccttctaccgcacgctggagggctttcgcctgctggtggagaaggagtggctgtccttcggccatcgcttcagccaccgtggagctcacaccctggccgggcagagcagcggcttcacacccgtcttcctgcagttcctggactgcgtacaccaggtccacctgcagttccccatggagtttgagttcagccagttctacctcaagttcctcggctaccaccatgtgtcccgccgtttccggaccttcctgctcgactctgactatgagcgcattgagctggggctgctgtatgaggagaaggaggaacgcaggggccaggtgccgtgcaggtctgtgtgggagtatgtggaccggctgagcaagaggacgcctgtgttccacaattacatgtatgcgcccgaggacgcagaggtcctgcggccctacagcaacgtgtccaacctgaaggtgtgggacttctacactgaggagacgctggccgagggccctccctatgactgggaactggcccaggggccccctgaacccccagaggaagaacggtctgatggaggcgctccccagagcaggcgccgcgtggtgtggccctgttacgacagctgcccgcgggcccagcctgacgccatctcttcgcctgctggaggagctgcagaggaggagacagagttgggccaacccgctgagcgctggaaggacacctgggaccgggtgaaggctgcacagcgcctcgagggccggccagacggccgtggcacccctagctccctccttgtgtccaccgcaccccaccaccgtcgctcgctgggtgtgtacctgcaggaggggcccgtgggctccaccctgagcctcagcctggacagcgaccagagtagtggctcaaccacatccggctcccgtcaggctgcccgctgcagcaccagcaccctgtacagccagttccagacagcagagagtgagaacaggtcctacgagggcactctgtacttagaagggggccttcatgaagccttggaaggcccgctggttcgtgctggacaagaccaagcaccagctgcgctactacgaccaccgtgtggacacagagtgcaagggtgtcatcgacttggcggaggtggaggctgtggcacctggcacgcccactatgggtgcccctaagactgtggacgagaaggccttctttgacgtgaagacaacgcgtcgcgtttacttacttctgtgcccaggacgtgccctcggcccagcagtgggtggaccggatccagagctgcctgtcggacgcctgagcctcccagccctgcccggctgctctgcttccggtcgttaccgaccactaggggtgggcagggccgccccggccatgtttacagccccggccctcgacagtattgaggccccgagcccccagcacttgtgtgtacagcccccgtccccgccccgccccgcccggccggccctaacttattttggcgtcacagctgagcaccgtgccgggaggtggccaaggtacagcccgcaatgggcctgtaaatagtccggccccgtcagcgtgtgctggtccagccagcggctgcaggcgagtttctagaaccagagtctatataaagagagaactaacgccacgctcctgtgcctgccttccccactccccggctgcctgctctcggcctacccagttgggtcccatctgcccctatccaggcccacctggcgggaggttggcatctttctcgtgagcctctcctggtgcctgggtccacccagctcggcctgcatgtccctgggagtgactttgctctgggggcggatcgagcaggaggcttcactggggacagcttgattccctccacgcctcagggctggtctaggggccggcacggctggagaggaagcccccatccctacccaggggatgcagaagctgacctcacagaggcttgggggtgaaagggtgggtggtcatttgaccccagaaggctgttgcaggtccagaggacacttgaggtggacgtcagtttctggctagacccgagctgaagggatggaggccggaggcgggggggggggggggacagtgggctcccaggggaatgcaggttgaccacatctggctcctgccaggcaacgagcagcatctggcagagtaaggggccaacgcccatgggggatggaccctctcagttcttgggaattctgccccaaaagtcctttccctggggtctcagagggcccccgtccttcccttcaggtgtcactgtggcccctcactgctcttttcctattcaaacctgagtcccaccaggcccagggcttcacctgctgagctgttgtgtccctgcctgtgacgaggcctggccaggggtgcaggagcagaaggtggggagggttatagacgctgcaaaggccaagagaacatctgagagtggcagctggtgacctggccagaggggctggtgaggggcagagaacctggatgaggctgggtccctcaggtggtcctctcaagtgggagttcgagcatcagttttttttagtgaggataaagttcttattacagctgcagaggcagggcccagtgctggcaggtggggggccaagaccctcccctggtgggacgttgaagccaaggatggccttggaccctgtcaggcccagcatggtcccgccacctcccccaccccacaggtggtgttgggacacctgggcgagatgtgagggtgggctcacttgagccactgaaaccagccaggtcttccctcaggccggacagatggcgcctgaccgaagttcctggcacctggaaaacccacaggtcagagtaaggggagaaaggaccctgccctccctgttccacgtctgtggggggagaggacaaatgccaggcacagggtaggcggcgagaacaaggcactcaatgtgtagctggggcagagactcggcctctggggagctgagcgggttccctccacccccaaccgtggtggaaagacaattcgctggggcggggtgggggtctggtctccacctgcccctcccactcagccactgaggacaaggtggggcccaggcttctgggagggggagctggcacaaaaggaagtcctggggttgatgtgtttgagcgttaggcgaagtggttccccccatcccccaaacggaaaaatgtcagtatttgctaagctgtagagacctgatgccgtgatgtggcctgttccgcctccacccattacacggggataacgctggggggtggcgggcccacaaaagaggtgctggaggagactctcccacccctggccgggccggggctttggggccggaaggttcacagtacgcggtttgtccgaacgtcacggcttttattgggagttggggctttggggtgccctgtcaggtgatcagaacattaaaaatggactcaacgtaaaaaaaaaaaaaaaaaa (SEQ ID NO: 665) Lpmkgccgtcagggccccagggagcgcggggcgccgctgctgctgttcttcggctcggtt NM_152230NM_027184 ctgtctaccgggcagcgccggggccggcggctgcggcggcagaggaacaggagccgggagccgcgttccgccgagagttgggcagaggagcgcccgcgccccggcggcgtcatgggccccctccccgcgcttcagttgggcaccagccgcgggattcccccgggcctcctcgcgcccgagcctgagcgaccctcgggttctccggcgccccctccctcgccctattttttttcctactctcgctgccgttaccgcttctgctctccgttatggcaacagagccaccatcccccctccgggtcgaggcgccgggccccccagaaatgcggacctcaccggcgatcgagtccacccctgagggcaccccgcagccggcgggcggccgactccgcttcctcaacggctgcgtgcccctctcgcatcaggtggccgggcacatgtacgggaaggacaaagtgggtatactgcaacatccagatggcacagttttgaaacagttacaaccacctccaaggggcccaagagagctggaattctataatatggtttatgctgctgaagttttgatggtgttcttctagagctacgaaaatatttgccaaaatattatggcatctggtcacctcccactgcaccaaacgatttatacctaaaactggaagatgtgacccataaatctttataagccctgtataatggatgtaaagataggccaaaaaagctatgatccttttgcctcatctgagaagattcagcaacaggtcagcaagtacccattaatggaagagattgggttcttggtgcttggcatgagggtttatcatgttcattccgatagctatgagacagaaaaccagcattacggaagaagcttaacaaaagaaactataaaggatggagtctccagattttttcataatgggtactgcttaagaaaagatgctgttgctgccagtattcagaagattgagaaaattctgcagtggtttgaaaaccagaagcagcttaatttttacgcaagttcattactctttgtaatgaaggttcatctcagccaaccactacaaaattgaatgacagaactttggcagaaaagtttttgtccaaaggacaactgtcagacacagaagtactagagtacaataataactttcatgtgttaagttccacagctaatggaaaaatagagtcttcagtgggcaaaagcttgtccaagatgtatgcgcgtcacaggaaaatatatacaaaaaagcatcacagtcagacttcattgaaagttgaaaatctggagcaagacaatgggtggaaaagcatgtcacaggaacatttaaatggaaatgtactttcccaactggaaaaagttttctaccatcttcccactggttgccaagagattgctgaagtagaagtgcgaatgatagattttgctcatgtgttccctagcaacacaatagatgagggatatgtttatgggctaaagcatttaatttctgtacttcgaagtatttaagacaattgaatcctctgagcagtctttttaaggggtgggccaatcataatgaagaggggcagtcaatatctgcacctttaatgctatgtaaaaaatttgtattatgagtcgacattttatttgtctttatacttttggaagaatggttaacttttttataatcttactcaggaaaactaactatttgttcattagaaaactatgaagaataaagaaacttaggaatgttaagcagggaatgtggtggtacatggcttaaacatcttttttggctcaagcaaaatgcaaaccattattcagtcattaagagtttagaagctttctgtagccaattcatgaaatctctgtccacccagccttgacaatgagccatatctaaaatattacattattagaacacctaccaaaatctcgaaagcacaggttgatgtccttagtattgctatgtatgaagttactaaaactggagaaaattctacttcagaaataagtactgtttaggtttttatattaaaagttcagaccagcatatcaaagggtgctccttagtgaaatgatttagaattgttgcattccaaaagcaggttttctctttaatttttacatctctctctcaaaatattatacttcatgaaaaagacaattgatgtggatgacaacaacaaagtcttgaaattaagggcacactaattgtccttactggggttaggggaagagagatattattttcttaggaacaattatattttcctttacaatctttcattcatgagaaaattggaatataaatttattacattgtgaaagtatcataaaccatatacctttgtatctaaatgcagcttcaaaaaagtaaataattgaagttttatttctcctctaaataacttgaatttttttctttaaaaatttatgtatttatatgtccccatttagttaagtggtagtgtaaatgttttgttgctaaaaacagtttctcagaattatagtaagcaatgaaagacaatatctaattaggttgttatcaaaaatactgtgtgtaaattagtccgtaatatagggtttggtgcgtatctataacatgcttctatttcactcttcctcaaaacagttttatattatgttgaccagtgaaattgtaacttaatttcatggggacaggggcagtgctacagttcctggaattaattagatttgtattatctttgtttcacacccaccaccttaaaaattaaatcaactagttatttgtcataaaaacatttaaaactttgagtcttcaaatacatttgatgttaatgctgccattacttgcacttccattcactaataacatttctaggtagttatcagttttgtcatattcctggaaaatattttggggttgtaaattctttctcctctttttcttctggagttacaaattgaatttttaaatccgagcacctttattgtggtgtggagaaaattatcacaattttatgtttattttaccttctcagccttctctgagggcactttgcaaatacctgagtccaaacagaagtaccaactaaatgctctatgaactctatccttagtaaatctattaaacctgaataatttaaaagatcatgttcattttgtaatagcaaaatttgatataattttttatttagaattggtgtatttatcatagggacttccaatttttcttcactttttgaatggatattggctatagttttatgttttaacgggaatgaatttcaagtcataataatcagaatttttagttaactttatcttttacaatatggattttgttgttatttggatagtggttcaataaatcttaagctcagataattaaacactattttgaatcttaacaagatactgaggctttttttgtatgggatgatatatacctatgtacaatgaatttaataaacttaagtattgtcagattttttgcacattttagctcaataaaatcttaatgttcaagatttttttatctgcatttggaaatacaattttgtaaaatcaatgtcttacctttttgatacaatagatcatgttttgtttttaataaagcaagaagcccttttatctgttgtttttcagggaagggattaacatttaattctgtttgtttacatttgttatcattgttatccaatgctcattttatgttgctttataagtaggcttaggtataacagaataagtatctgtttatctaatctacatgtgactatcttagtctctctcggtcacttaatattatgctgaaatttaccactgtggggatgaatgatcgctattcaccaagtatatttgaacatgtaaatgcttaagaaataagcataatgcggatatagtttgggttaataggattctcatagttttttttcccctatgaaacataagtaatgattttagtgtatttcttatggaatacactcatttaaaaaggactttaagaaattgtggatgtgaataatacctttctctaataaaaatttaaattgtataatagttttataatatttacattaattgatattttaatatggatagacattgcatagattcaaataaattaaaatcaatgataaatgctaaatattttatctaaatagtttttcaagaaacagttatggaaatgtgtatattaaatggctctaatgtggagcttgtggtatttcaactcagtattcattattagttgtgtgtctggaaagattgtacttacttttcctctttacactacagtttgctcttatggggctctaaactgtttaactgaagaaccttcgtctgtattttgattgagcataatttagtattttatgatttccaagatgatgttcttatgtctatcaagtctatgtatcaaatttataacatcatttaagaaaaaggaatttccacagatacttcagttgcaattttttgtttcatgctactgaaaatacatttgtttctaggggttggaatattatagaagatgtaggatgaaagaaaacgatagaacaacgaaagaattctgtttatgaaattacaggaattgtgtccactatggtaaagcattgtcatttttagtacattttctcttagtagtttggcattttatactttaaaacttgttttgctttaaaaattgtttataatgcttaccctctttctccagtgcctttagtcttgatttgatatgtttgtaccctcagttaccctttctattacatgtttttgatgttttcatagcctaggaaacatcgattcctttttaataattgtcaatctgattatttaaagaggtaacaattatctgttaatgctttggaaaaacaagtagggttgcctttggaggccaggcttcttagttcattcaaaaatattccttggatttatgccatgtattaagcatttttagcccccagtattacaactgtgaaccaaacggataaggccctaaccattttcagcattctctttggatggggtgggattggggacttaattaaaatagagatatagaaaaataggcatctaaataagataataagtgtggggttgaaatgaagcatctaacaatagttgaagttagaagtaatattttacagtattgtaacctctatttaagtttgggtattttgttacagatagcataaaaaagccttaatttttcactttccttgctggcaaaggtacatttatttagactgtccatttaaagtaatgtttaacataaacattactgtgaaaaacattccattacatattcccaagcaaatgagctgcatcttcatactgtattttacaatttagtacaacagttttaggcctcaatcttaacatcactggtattttaaatttggcaatgaatatgaaattacttttgacttacagattgattatattattactttgaaaatgcattaatttcttagaaaagtttggagcctctatctttttttgagaaatacttaaattctcattacttatattaatagcctgtactaagtgatttgtcatcttaagtttaaattttttacctactgtccacttaaatataatttaacagtctgtaaagtgaaatagttttaagtatgatgtatgatgcacctgcatataaatgaaaatggcgtgcacaaagacactttactatgggaactgtactggaagatttatgaaagcatgtgaaattgcacctgtatttagtcacagttactttggtttaaatgtataaatgtctttagggtttttttttaaatgtgtttgtaatttgtactattgtgggggtatacttggactgcaggggttattgtcaatgtgtgatttgtgtttttattttatagaatcatctaatgtgatataccaatttttataagtgatatttacataattctaataactgtatatttgacaacctattatttatgattgcattggaa (SEQ ID NO: 666) Rock1gctggttccccttccgagcgtccgcgccccgcatgcgcagtctgccccggcggtctc NM_005406NM_009071 gctggttccccttccgagcgtccgcgccccgcatgcgcagtctgccccggcggtctccgtttgtttgaacaggaaggcggacatattagtccctctcagcccccctcgccccaccccccaggcattcgccgccgcgactcgccctttccccggctgggaccgcagcccctcccagaagctcccccatcagcagccgccgggacccaactatcgtcttcctcttcgcccgctctccagcctttcctctgctaagtctccatcgggcatcgacctcgccctgccccaccggacaccgtagcagcagccccagcagcgacgggacaaaatgggagagtgaggctgtcctgcgtgcaccagctcgtggccgagactgatcggtgcgtcgggccgggccgagtagagccggggacgcggggctagaccgtctacagcgcctctgagcggagcgggcccggcccgtggcccgagcggcggccgcagctggcacagctcctcacccgccctttgctttcgcctttcctcttctccctcccttgttgcccggagggagtctccaccctgcttctctttctctacccgctcctgcccatctcgggacggggacccctccatggcgacggcggccggggcccgctagactgaagcacctcgccggagcgacgaggctggtggcgacggcgctgtcggctgtcgtgaggggctgccgggtgggatgcgactttgggcgtccgagcggctgtgggtcgctgttgcccccggcccggggtctggagagcggaggtcccctcagtgaggggaagacgggggaaccgggcgcacctggtgaccctgaggttccggctcctccgccccgcggctgcgaacccaccgcggaggaagttggttgaaattgctttccgctgctggtgctggtaagagggcattgtcacagcagcagcaacatgtcgactggggacagttttgagactcgatttgaaaaaatggacaacctgctgcgggatcccaaatcggaagtgaattcggattgtttgctggatggattggatgctttggtatatgatttggattttcctgccttaagaaaaaacaaaaatattgacaactttttaagcagatataaagacacaataaataaaatcagagatttacgaatgaaagctgaagattatgaagtagtgaaggtgattggtagaggtgcatttggagaagttcaattggtaaggcataaatccaccaggaaggtatatgctatgaagcttctcagcaaatttgaaatgataaagagatctgattctgcttttttctgggaagaaagggacatcatggcttttgccaacagtccttgggttgttcagcttttttatgcattccaagatgatcgttatctctacatggtgatggaatacatgcctggtggagatcttgtaaacttaatgagcaactatgatgtgcctgaaaaatgggcacgattctatactgcagaagtagttcttgcattggatgcaatccattccatgggttttattcacagagatgtgaagcctgataacatgctgctggataaataggacatttgaagttagcagattttggtatttgtatgaagatgaataaggaaggcatggtacgatgtgatacagcggttggaacacctgattatatttcccctgttagtattaaaatcccaaggtggtgatggttattatggaagagaatgtgaaggtggtcggttggggtatttttatacgaaatgcttgtaggtgatacacctttttatgcagattctaggttggaacttacagtaaaattatgaaccataaaaattcaatacctttcctgatgataatgacatatcaaaagaagcaaaaaaccttatttgtgccttccttaagacagggaagtgaggttagggcgaaatggtgtagaagaaatcaaacgacatctcttcttcaaaaatgaccagtgggcttgggaaacgctccgagacactgtagcaccagttgtacccgatttaagtagtgacattgatactagtaattttgatgacttggaagaagataaaggagaggaagaaacattccctattcctaaagctttcgttggcaatcaactaccttttgtaggatttacatattatagcaatcgtagatacttatcttcagcaaatcctaatgataacagaactagctccaatgcagataaaagcttgcaggaaagtttgcaaaaaacaatctataagctggaagaacagttgcatttatgaaatgcagttaaaagatgaaatggagcagaagtgcagaacctcaaacataaaactagacaagataatgaaagaattggatgaagagggaaatcaaagaagaaatctagaatctacagtgtctcagattgagaaggagaaaatgttgctacagcatagaattaatgagtaccaaagaaaagctgaacaggaaaatgagaagagaagaaatgtagaaaatgaagtttctacattaaaggatcagttggaagacttaaagaaagtcagtcagaattcacagcttgctaatgagaagctgtcccagttacaaaagcagctagaagaagccaatgacttacttaggacagaatcggacacagctgtaagattgaggaagagtcacacagagatgagcaagtcaattagtcagttagagtccctgaacagagagttgcaagagagaaatcgaattttagagaattctaagtcacaaacagacaaagattattaccagctgcaagctatattagaagctgaacgaagagacagaggtcatgattctgagatgattggagaccttcaagctcgaattacatctttacaagaggaggtgaagcatctcaaacataatctcgaaaaagtggaaggagaaagaaaagaggctcaagacatgcttaatcactcagaaaaggaaaagaataatttagagatagatttaaactacaaacttaaatcattacaacaacggttagaacaagaggtaaatgaacacaaagtaaccaaagctcgtttaactgacaaacatcaatctattgaagaggcaaagtctgtggcaatgtgtgagatggaaaaaaagctgaaagaagaaagagaagctcgagagaaggctgaaaatcgggttgttcagattgagaaacagtgttccatgctagacgttgatctgaagcaatctcagcagaaactagaacatttgactggaaataaagaaaggatggaggatgaagttaagaatctaaccctgcaactggagcaggaatcaaataagcggctgttgttacaaaatgaattgaagactcaagcatttgaggcagacaattgaaaaggtttagaaaagcagatgaaacaggaaataaatactttattggaagcaaagagattattagaatttgagttagctcagcttacgaaacagtatagaggaaatgaaggacagatgcgggagctacaagatcagcttgaagctgagcaatatttctcgacactttataaaacccaggtaaaggaacttaaagaagaaattgaagaaaaaaacagagaaaatttaaagaaaatacagttaactacaaaataaaaaaaaaactcttgctactcagttggatctagcagaaacaaaagctgagtctgagcagttggcgcgaggccttctggaagaacagtattttgaattgacgcaagaaagcaagaaagctgcttcaagaaatagacaagagattacagataaagatcacactgttagtcggcttgaagaagcagagaaaatgaagaaggcagaggaagaatataaactggagaaggaggaggagatcagtaatcttaaggctgcctttgaaaagaatatcaacactgaacgaacccaaaaacacaggctgttaacaaattggcagaaataatgaatcgaaaagattttaaaattgatagaaagaaagctaatacacaagatttgagaaagaaagaaaaggaaaatcgaaagctgcaactggaactcaaccaagaaagagagaaattcaaccagatggtagtgaaacatcagaaggaactgaatgacatgcaagcgcaattggtagaagaatgtgcacataggaatgagcttcagatgcagttggccagcaaagagagtgatattgagcaattgcgtgctaaacttttggacctctcggattctacaagtgttgctagttttcctagtgctgatgaaactgatggtaacctcccagagtcaagaattgaaggttggctttcagtaccaaatagaggaaatatcaaacgatatggctggaagaaacagtatgttgtggtaagcagcaaaaaaattttgttctataatgacgaacaagataaggagcaatccaatccatctatggtattggacatagataaactgtttcacgttagacctgtaacccaaggagatgtgtatagagctgaaactgaagaaattcctaaaatattccagatactatatgcaaatgaaggtgaatgtagaaaagatgtagagatggaaccagtacaacaagctgaaaaaactaatttccaaaatcacaaaggccatgagtttattcctacactctaccactttcctgccaattgtgatgcctgtgccaaacctctctggcatgtttttaagccaccccctgccctagagtgtcgaagatgccatgttaagtgccacagagatcacttagataagaaagaggacttaatttgtccatgtaaagtaagttatgatgtaacatcagcaagagatatgctgctgttagcatgttctcaggatgaacaaaaaaaatgggtaactcatttagtaaagaaaatccctttagaatccaccatctggttttgttcgtgatcccctcgaacgctttctacaagatccactgcaaatcagtctttccggaaagtggtcaaaaatacatctggaaaaactagttaaccatgtgactgagtgccctgtggaatcgtgtgggatgctacctgataaaccaggatctttaaccatgcagagcagacaggctgtactttgacacaaatatcacaggcttcagggttaagattgctgtttttctgtccttgctttggcacaacacactgagggttttttttattgcgggtttgcctacaggtagattagattaattattactatgtaatgcaagtacagttgggggaaagcttaggtagatatattttttttaaaaggtgctgcctttttggatttataagaaaatgcctgtcagtcgtgatagaacagagttttcctcatatgagtaagaggaagggactttcactttcaagtggaacagccatcactatcaagatcagctcatggaaggagtaaagaaaatatctcaaaatgagacaaactgaagttttgttttttttttaatgacttaagtttttgtgctcttgcaagactatacaaaactattttaagaaagcagtgatatcacttgaacttcagtgccctcactgtagaatttaaaagccttactgttgattgcccatgttggacttgatggagaaattaaatatctttcatttttgcKtttcaaaatactgtatatgtttcagcaagtttggggaatgggagaggacaaaaaaaagttacatttaatctatgcatttttgccaagccatattgagttattttactactagagacattaggaaactaactgtacaaaagaaccaagtttaaaagcattttgtggggtacatcatttctataattgtataatgtatttctttgtggttttaaatgataaagacattaagttaacaaacatataagaaatgtatgcactgtttgaaatgtaaattattcttagaacactttcaatgggggttgcattgtccttttagtgccttaatttgagataattattttactgccatgagtaagtatagaaatttcaaaaaatgtattttcaaaaaattatgtgtgtcagtgagtttttcattgataattggtttaatttaaaatatttagaggtttgttggactttcataaattgagtacaatctttgcatcaaactacctgctacaataatgactttataaaactgcaaaaaatgtagaaggttgcaccaacataaaaaggaaatatggcaatacatccatgatgttttccagttaacataggaattaccagataaatactgttaaactcttgtccagtaacaagagttgattcatatggacagtatgatttattgtttatttttttaaccaaatacctcctcagtaatttataatggctttgcagtaatgtgtatcagataagaagcactggaaaaccgatcgtctctaggatgatatgcatgtttcaagtggtattgaaagccgcactgatggatatgtaataataaacatatctgttattaatatactaatgactctgtgctcatttaatgagaaataaaagtaatttatggatgggtatctttaatttttactgcaaaaatgtttgtgaaattccatggttagattaaagagctagggagaggaaaattt (SEQ ID NO: 667)Stk17b gaacggcgatgccccagacgcggctgcagttttcaaaccgcgactgcaagcttcggNM_004226 NM_133810tagtcctctccgctgctgtcgccaggagtcacttcacgagtagccaggtcacaaccgtcggcccttgtctggaaaagtaaaagtggatcctgccacgttcggagctccctggcgcctcgtccggctggagctagagatctcgtcctgtggcggcccccggcgtggggcgggacagcggccccctggagggggcagtcccgggagaacctgcggcggccggagcggtaaaaataagtgactaaagaagcagacctgggaatcacctaacatgtcgaggaggagatttgattgccgaagtatttcaggcctactaactacaactcctcaaattccaataaaaatggaaaactttaataatttctatatttcttacatctaaagagctagggagaggaaaatttgctgtggttagacaatgtatatcaaaatctactggccaagaatatgctgcaaaatttctaaaaaagagaagaagaggacaggattgtcgagcagaaattttacacgagattgctgtgcttgaattggcaaagtcttgtccccgtgttattaatcttcatgaggtctatgaaaatacaagtgaaatcattttgatattggaatatgctgcaggtggagaaattttcagcctgtgtttacctgagttggctgaaatggtttctgaaaatgatgttatcagactcattaaacaaatacttgaaggagtttattatctacatcagaataacattgtacaccttgatttaaagccacagaatatattactgagcagcatataccctctcggggacattaaaatagtagattttggaatgtctcgaaaaatagggcatgcgtgtgaacttcgggaaatcatgggaacaccagaatatttagctccagaaatcctgaactatgatcccattaccacagcaacagatatgtggaatattggtataatagcatatatgttgttaactcacacatcaccatttgtgggagaagataatcaagaaacatacctcaatatttctcaagttaatgtagattattcggaagaaactttttcatcagtttcacagctggccacagactttattcagagccttttagtaaaaaatccagagaaaagaccaacagcagagatatgcctttctcattcttggctacagcagtgggactttgaaaacttgtttcaccctgaagaaacttccagttcctctcaaactcaggatcattctgtaaggtcctctgaagacaagacttctaaatcctcctgtaatggaacctgtggtgatagagaagacaaagagaatatcccagaggatagcagcatggtttccaaaagatttcgtttcgatgactcattacccaatccccatgaacttgttcagatttgctctgtttagcacttttttctttgactcatttggactgaatttgaaattttatatccactccagtgagattatgatttgtagcttcatatatgacatgtttatattgtaaatgcacttttccatggaataatttagggaagtgttttaatgttaaattactagttgctagcatgttatgatttcatatcctgagatagctctgcagataagaaaatatttaaatatatgacaaaaagtaaaattgtacatgtgagtttacatgttaatgaaataattcaacttcaaatgaacttaccagaatgttttgcatatcaacaaaaaaagtggcttgagttttattatagttggtgtaaactgaacacagtgaagacattggaatttaataggttctctctctaaggtgactcttataccatgcctctatcaacataatttgtttaggaaagcagtatgaagtttaagccaaaataatttctactttatagatgctcaagagacattttacaattgaaaatgtctttcaattacaaatattttgaaacttcgtaagattttcattctctgtggtctgttatatgagagagatcctttttactagagcaaagagggagttagaaacctgatcagggatattctttacaagttggagcagaggaaagagtagcatgccttcgtattttaacgcaaatgtctttttcctcctcccaacctacttgagatctgataaggtctggaagatggagatatttggtatgcaagtgtagagttttttaatcctccagaatttctagagtagaagatacttaggtatagttaaatattagtatttttagtcaaacatatttattaattgaatatagaagaaaatgttgacacactcagacagcttactgaattttagatgtcttctgcatcttagaatacaagccagtcattcagagttctaaaagtatgcataaaaaattacagcaccggtaggtctattaacacagtgcccgagtcagcggtagcaagactgatgtgatcataaaacatgacatcaggctcgtctgaagttcttgtgtgaaattcctagtgagtgaggaggctcagcttaaagccatctgcagagtggcccctcattgtggtcttttgctgggaccaatgcaagagactagggagagcaaaatgtttgcttatggctagagactatatccagccctaatgatggggaaagttagtccttttcgggtaatcttttatgaattttcacctgatgaccgttatattggtctgttatcatgttacgataactgtgatctcatgaccatgttgctgtatcagaagaaatagtttgacaaatggtaacattcaacctgatgttccccctttagacctttaacttctcaaaattttggtaagtttccaaattctttaataataacttaaaactttttgaataactatcaggtcactttatttgaccacatggtgaattcctttaatgtcttcagcatttgttaaggaaaagttttctctacttgtgtgtgtatgtgtgcacatgtgtgtatgtacaggtgtatgtatatatctatagatagatacaatacattctttagacacttttcaagattctttgctgtggtatttttgtgctcaactcaggtgccaaaggagattttttttttttttttttttttgagatggagttttgctctgtactcaggctggagtgcagtggcatgatctcagctcacggcaacctctgcctcccgggttcaagcaattctcctgtctcagcctcctgagtagttgggattacaggcgcatgccaccgtgcccagctaatttttgtatttttagtagagacggggtttcaccatgttggccaggctggtcacaaactcctgacttcaagtgatccacccgcctcggcctcccaaagtgctgggattacaggcgtgagccactgcgcccccgcccaggagctcttttcttatgacatataaattatgacatttatattctttatatgactttatgttctcttcttatgacatttaaattctttaagtagtttgttggtccaataaactagacgttgtataatctaaattgagcccttgtatatctaaaactgatgagttgtttctaaattgttgattgtccatttacttgcctttggtattaagataatgcaagtaaagtttagtaagtcattggataatgaaatgattatgtttctgaagaccatattatatttttaatttttagaggaatcatgccatcccccaaaaaatcaagaaatatttgaatttgaaattataagttcatttgttaaaagacatttttacaaatgtctgaaaatcttaaaatactttacatctacctttaagtagtagaatacagagctgtaaatttccatgccttttttcctgatattaagttttatagtaaaaaagcaactagtgattgcacaaagaatataaaaatccactctttttacaaaggtgtgaatttaaataacgttattgattggaatatgaaaatagaccaatcatttaagagctttttagcaaatgattcaattcttactctttttctcccaagattgaaaagcataatgtatttctctaaagtaggaatctagagagcccctataagtggacaaatgtcagtaacacttgaacacatgagaagataagtgttatgttgtgataatttaaagttaaatttgctttttgggtaggatccctaaatagatgggatttttaaatagatgatatatagatgacaattgcaattgtcattttaattattttccctacagtaaagaacctagctctgagcagtgaaattgtaatggcactttaaaggaagtaagccgttaactgactctagtggagcgatctccaactgttttggcactagggacgggttttgtggaagaaaatttttccacaggactgggggtttagggggatggtttcaggatgattcaagtacattacatttatcattagattctcataaggagcatgcaacctagatctcttgcacgtgtggttcacagcaggattcgagctcctttgagaatctaatgccatggctgatctaacaggaaactgagctcaggcagtaatgcttggcaccgccccccaccttctatgcagcccggtcgtggcctggggactggggacccctgctctagtcagtaataaggtacttgtgccagaatataaatcaacacattgcttcctttatcaaagaagtcttgttatttaaaaaaagtcaactgagccagtatgattagtgatgtaattgattttcattctggcacaagcctctttcattctggacagctcacaaatagttaatggaccatgctttgaatagccttcctctaagcaacatttataaatactgatattttagaactgtaacatttcttctgtttatttttgaattttcagtttgatatcttgtccttattcattgttgtataaacaactgtactttaatttcaagtagtattaaaagtatttcacttcagtttggggggattattatcaatttataattttatttaaagtattttaaagaaaattgtaaattttccataaattacaacttcctgccatattttattaaataataatcttgcttaaggcatatagacagacattattatgagtattccagtaaaaaaaatctacatcaacttgaccattctggctaaaaattaaaaagcacttttttatatctgtggttgtcatttgtttcaaagcatttctaaatttattgttcttaaaagtatgtctgcatgttctagcctttgacctaggtcatctatgaaccctctttgtgtctaataaacatatctgtaaaggcaaaaaaaaaaaaaaaaaa (SEQ ID NO: 668) Mast2taggcaggcggctgagccggcggcgggtggcctgcccaacgtgtgctgggtggg NM_015112 NM_agaaggcgaggcgtcagcgatgctgtctcttccgtgaggagcgcagaggaggtcg 001042743cggcgccggaggccccagaaggctcgaaggcgccgcgggctggggtcggtggcttagggagcccgtccggccatggtggccgcgggtggtggttggcgcggctgcgctgcggcccggggcagtgcggagccgggacagtcgcggcgctgacgcccgcgggccccagctgcagatatgaagcggagccgctgccgcgaccgaccgcagccgccgccgcccgaccgccgggaggatggagttcagcgggcagcggagctgtctcagtctttgccgccgcgccggcgagcgccgcccgggaggcagcggctggaggagcggacgggccccgcggggcccgagggcaaggagcaggatgtagtaactggagttagtcccctgctcttcaggaaactcagtaatcctgacatattttcatccactggaaaagttaaacttcagcgacaactgagtcaggatgattgtaagttatggagaggaaacctggccagctctctatcgggtaagcagctgctccctagtccagcagtgtacatagcagtgtgggacaggtgacttggcagtcgtcaggagaagcatcaaacctggttcgaatgagaaaccagtcccttggacagtctgcaccttctcttactgctggcctgaaggagttgagccttccaagaagaggcagcttttgtcggacaagtaaccgcaagagcttgattgtgacctctagcacatcacctacactaccacggccacactcaccactccatggccacacaggtaacagtcctttggacagcccccggaatttctctccaaatgcacctgctcacttttcttttgttcctgcccgtaggactgatgggcggcgctggtctttggcctctttgccctcttcaggatatggaactaacactcctagctccactgtctcatcatcatgctcctcacaggaaaagctgcatcagttgcctttccagcctacagctgatgagctgcactttttgacgaagcatttcagcacagagagcgtaccagatgaggaaggacggcagtccccagccatgcggcctcgctcccggagcctcagtcccggacgatccccagtatcctttgacagtgaaataataatgatgaatcatgtttacatagaaagattcccaaaggccaccgcacaaatggaagagcgactagcagagtttatttcctccaacactccagacagcgtgctgcccttggcagatggagccctgagctttattcatcatcaggtgattgagatggcccgagactgcctggataaatctcggagtggcctcattacatcacaatacttctacgaacttcaagataatttggagaaacttttacaagatgctcatgagcgctcagagagctcagaagtggcttttgtgatgcagctggtgaaaaagctgatgattatcattgcccgcccagcacgtctcaggaatgcctggagtttgaccctgaagagttctaccaccttttagaagcagagagggccacgccaaagagggacaagggattaaatgtgacattccccgctacatcgttagccagctgggcctcacccgggatccatagaagaaatggcccagttgagcagctgtgacagtcctgacactccagagacagatgattctttttgagggccatggggcatctctgccatctaaaaagacaccctctgaagaggacttcgagaccattaagctcatcagcaatggcgcctatggggctgtatttctggtgcggcacaagtccacccggcagcgctttgccatgaagaagatcaacaagcagaacctgatcctacggaaccagatccagcaggccttcgtggagcgtgacatactgactttcgctgagaacccctttgtggtcagcatgttctgctcctttgataccaagcgccacttgtgcatggtgatggagtacgttgaagggggagactgtgccactctgctgaagaatattggggccctgcctgtggacatggtgcgtctatactttgcggaaactgtgctggccctggagtacttacacaactatggcatcgtgcatcgtgacctcaagcctgacaacctcctaattacatccatggggcacatcaagctcacggactttggactgtccaaaattggcctcatgagtctgacaacgaacttgtatgagggtcatattgaaaaggatgcccgggaattcctggacaagcaggtatgcgggaccccagaatacattgcgcctgaggtgatcctgcgccagggctatgggaagccagtggactggtgggccatgggcattatcctgtatgagttcctggtgggctgcgtccctttttttggagatactccggaggagctattgggcaggtgattagtgatgagattgtgtggcctgagggtgatgaggcactgcccccagacgcccaggacctcacctccaaactgctccaccagaaccctctggagagacttggcacaggcagtgcctatgaggtgaagcagcacccattctttactggtctggactggacaggacttctccgccagaaggctgaatttattcctcagttggagtcagaggatgatactagctattttgacacccgctcagagcgttaccaccacatggactcggaggatgaggaagaagtgagtgaggatgcctgccttgagatccgccagttctcttcctgctctccaaggttcaacaaggtgtacagcagcatggagcggctctcactgctcgaggagcgccggacaccacccccgaccaagcgcagcctgagtgaggagaaggaggaccattcagatggcctggcagggctcaaaggccgagaccggagctgggtgattggctcccctgagatattacggaagcggctgtcggtgtctgagtcatcccacacagagagtgactcaagccctccaatgacagtgcgacgccgctgctcaggcctcctggatgcgcctcggttcccggagggccctgaggaggccagcagcaccctcaggaggcaaccacaggagggtatatgggtcctgacacccccatctggagagggggtatctgggcctgtcactgaacactcaggggagcagcggccaaagctggatgaggaagctgttggccggagcagtggttccagtccagctatggagacccgaggccgtgggacctcacagctggctgagggagccacagccaaggccatcagtgacctggctgtgcgtagggcccgccaccggctgctctctggggactcaacagagaagcgcactgctcgccctgtcaacaaagtgattccccgttggccagccccatgtccccacattctcagtcgtccaacccatcatcccgggactcttctccaagcagggacttcttgccagcccttggcagcatgaggcctcccatcatcatccaccgagctggcaagaagtatggcttcaccctgcgggccattcgcgtctacatgggtgactccgatgtctacaccgtgcaccatatggtgtggcacgtggaggatggaggtccggccagtgaggcagggcttcgtcaaggtgacctcatcacccatgtcaatggggaacaaggtggccatttcaacaactcccctggagaacacatccattaaagtggggccagctcggaagggcagctacaaggccaagatggcccgaaggagcaagaggagccgcggcaaggatgggcaagaaagcagaattaaggagctccctgttccgcaagatcaccaagcaagcatccctgctccacaccagccgcagcctttcttcccttaaccgctccttgtcatcaggggagagtgggccaggctctcccacacacagccacagcattccccccgatctcccactcaaggctaccgggtgacccccgatgctgtgcattcagtgggagggaattcatcacagagcagctcccccagctccagcgtgcccagttccccagccggctctgggcacacacggcccagctccctccacggtctggcacccaagctccaacgccagtaccgctctccacggcgcaagtcagcaggcagcatcccactgtcaccactggcccacaccccttctcccccacccccaacagcttcacctcagcggtccccatcgcccctgtctggccatgtagcccaggcctttcccacaaagcttcacttgtcacctcccctgggcaggcaactacacggcccaagagtgcggagccaccccgttcaccactactcaagagggtgcagtcggctgagaaactggcagcagcacttgccgcctctgagaagaagctagccacttctcgcaagcacagccttgacctgccccactctgaactaaagaaggaactgccgcccagggaagtgagccctctggaggtagttggagccaggagtgtgctgtctggcaagggggccctgccagggaagggggtgctgcagcctgctccctcacgggccctaggcaccctccggcaggaccgagccgaacgacgggagtcgctgcagaagcaagaagccattcgtgaggtggactcctcagaggacgacaccgaggaagggcctgagaacagccagggtgcacaggagctgagcttggcacctcacccagaagtgagccagagtgtggcccctaaaggagcaggacagagtggggaagaggatcctttcccgtccagagaccctaggagcctgggcccaatggtcccaagcctattgacagggatcacactggggcctcccagaatggaaagtcccagtggtccccacaggaggctcgggagcccacaagccattgaggaggctgccagctcctcctcagcaggccccaacctaggtcagtctggagccacagaccccatccctcctgaaggttgctggaaggcccagcacctccacacccaggcactaacagcactttctcccagcacttcgggactcacccccaccagcagttgctctcctcccagctccacctctgggaagctgagcatgtggtcctggaaatcccttattgagggcccagacacggcatccccaagcagaaaggcaaccatggcaggtgggctagccaacctccaggatttggaaaacacaactccagcccagcctaagaacctgtctcccagggagcaggggaagacacagccacctagtgcccccagactggcccatccatcttatgaggatcccagccagggctggctatgggagtctgagtgtgcacaagcagtgaaagaggatccagccctgagcatcacccaagtgcctgatgcctcaggtgacagaaggcaggacgttccatgccgaggctgccccctcacccagaagtctgagcccagcctcaggaggggccaagaaccagggggccatcaaaagcatcaggatttggctttggttccagatgagcttttaaagcaaacatagcagttgtttgccatttcttgcactcagacctgtgtaatatatgctcctggaaaccatcaaaaaaaaaaaaaaaaaa (SEQ ID NO: 669) Pdp1agagtgggcaggccgggggtgagggctcgcgctccgggagctgcacggggctgc NM_ NM_gtggaaagagcgccgagcggtggcgtcgttgtcgccccctcctcgtcgggaagaat 001161779001098231 cgtttggtctcctgccgtgcccggttcgtattccctactccctgccacgagccgccccgtccgggatcctccacccgtccaaagttgtgagggggcgccgggcgtgctcgcggatcggcggccgcgggcgtgcggagggctggacgagccctggagcgccaggagaatgtgtgtgtgtcccgggcccagacgaattggaatcccagtcagaagttccagcctgccactgttctctgatgccatgccagcaccaactcaactgttttttcctctcatccgtaactgtgaactgagcaggatctatggcactgcatgttactgccaccacaaacatctctgttgttcctcatcgtacattcctcagagtcgactgagatacacacctcatccagcattttgctaccttttgcaggccaaaggagaactggtggcagtacacccaaggaaggagatatgcttccacaccacagaaattttacctcacacctccacaagtcaatagcatccttaaagctttatgaatacagtttcaaagtgccagaatttgacggcaaaaatgtcagttctatccttggatttgacagcaatcagctgcagcaaatgcacccattgaggaccggagaagtgcagcaacctgcttgcagaccagagggatgcttttgggggtttttgatggccatgcaggttgtgcttgttcccaggcagtcagtgaaagactcttttattatattgctgtctctttgttaccccatgagactttgctagagattgaaaatgcagtggagagcggccgggcactgctacccattctccagtggcacaagcaccccaatgattactttagtaaggaggcatccaaattgtactttaacagcttgaggacttactggcaagagcttatagacctcaacactggtgagtcgactgatattgatgttaaggaggctctaattaatgccttcaagaggcttgataatgacatctccttggaggcgcaagttggtgatcctaattcttttctcaactacctggtgcttcgagtggcattttctggagccactgcttgtgtggcccatgtggatggtgttgaccttcatgtggccaatactggcgatagcagagccatgctgggtgtgcaggaagaggacggctcatggtcagcagtcacgctgtctaatgaccacaatgctcaaaatgaaagagaactagaacggctgaaattggaacatccaaagagtgaggccaagagtgtcgtgaaacaggatcggctgcttggcttgctgatgccatttagggcatttggagatgtaaagttcaaatggagcattgaccttcaaaagagagtgatagaatctggcccagaccagttgaatgacaatgaatataccaagtttattcctcctaattatcacacacctccttatctcactgctgagccagaggtaacttaccaccgattaaggccacaggataagtttctggtgttggctactgatgggttgtgggagactatgcataggcaggatgtggttaggattgtgggtgagtacctaactggcatgcatcaccaacagccaatagctgttggtggctacaaggtgactctgggacagatgcatggccttttaacagaaaggagaaccaaaatgtcctcggtatttgaggatcagaacgcagcaacccatctcattcgccacgctgtgggcaacaacgagtttgggactgttgatcatgagcgcctctctaaaatgcttagtcttcctgaagagcttgctcgaatgtacagagatgacattacaatcattgtagttcagttcaattctcatgttgtaggggcgtatcaaaaccaagaatagtgagtggctctttcactggcaattctcaaatgatatacatttaaagggcagattttttaaaaagatactactataataaacatttccagttggtcattctaagcatttacccttttgatactctagctagtcaggtactccaaattgactttgcagcagggtggcagggtcaggagagtctggtcctgcctagctcagatttcatggcacctgcacttgaagcaagtcacttctttatcacaggtgtcttgaaacattagcttcttttaccaacctgagaaaattaggatgacctggcaaataagatcagaataggccaaaagcaagtatcttgctgtgtgtagtctcttggttaaagtgaagaaacagtactgttcacacctttcttcactgagattccagtgtacatgagaacatatatttattgcatgattttctagatacacagtctatgcattattcatatacatttattttagcctaaagtggttttcaaatccagttcttcaagccataaatgaccaagatccaagcaatctgaatttgtttttgtgaaatttgactggaatgcttcttaagtggaataactatactccgttatccacccgatttcctaatgtaattgaaagattttctattttgccacacacttggagacaataagggtttttagttttatctactcttctattgaagttaaagaaagaaaaaaagatttttttatttgtattaatgaaaagctttagtttaaaataaggagatccagaataaaaagaagagactgatctcttcaattattgtcatctgtagccaccttgcacatcactcttatgtaatccccaaaggcttggcatgccgtaagtgtgtggtgggtagactgctgccggggaatcgtacttcttatttagtaatgataagacttttcattatttttggaattttaaagatgacataaataagtttaaatatcaattttggggagtaaggtttaatattgccatcgggtattgagacaggaggaagtttctgtttttctccatttagacataggtcaattaaaatatttgggtttaaaatgactaaatgctttaaacatattgtagcttaagatatatgtgttaagatatatacatgagaaacttttaaaaggtaactactgtgcatgcctgatgcttaatagaatacttagtggcatcaaatgtttgcagcagtctccataattatattcagtcccttctaatactgtatcaatgtaaatgaaataaatatttttcaaattggctttttgatatgcatcaagtggcattttgttcctgtgtttaatagtgatagtatacagctgtgcacatattgtcatcaatattctagcatcactgttaaggctgtgattatgtttgatattcacctggattttaatacaagccaatatcagcttcccattgtgtaataacttgggtgtttaggagtcttttcacattttttggggatatgaactagatgttcaagaactccttctggactgtggatactgaatcagtgtactattggctgcagaatagtttcaattgaaaatagactcaggaagattgctgctcagaatatcatataatgtttattttttgaggtgtttttgtttttatttgtgtgtttattttttttaagtcagcttggaacttttttcctgggtagtatttgggagagggaaaggctgtactatatatttatttctaaatgttttgactgggcatttttcttttaatgaaatatgtggactgctctagcaaaccctattttcagctactatttgaatattcttgaacaccaccactgaagagtttcatatacaccaaataatgtctcatctctatagtacagggaatataaaattggtttcctgtggtcatgatcaagatagtagtattattacacaagaaacttggtctgcagtctggaagcttgtctgctctatagaaatgaaaatgcagcatgaagttgacattgtggaaatgaaagtaattgggtattagaaatctgaaagtactgtcatctaaaagcaattgtgattttattgtaattggttgtcactgttgtacggtgtctagaattaaagaatacatgtaaactttcatggtatttagcctttcttaaatttttttaaaatttaaactttctaacctatgtattcaacttctgtatttataataatcagtggttcatgttatataatacacccttaactagttaaatggaatgttggtatggtacagagtaccatattgctaagaaaactgtcttataaaagatgtatatgtgtgaagacatgaaagtttaatgtacagaatggttggagaaatgcctatggtgaattaaagcttcatatctgctactgaaaaaaaaaaaaaaa (SEQ ID NO: 670) Yes1ggaggaggtggagagtgaggcggaggcgtggggagcccgggaactccctcctcc NM_005433NM_009535 tgaagtaacgcgtcccgggccggctagccgtcgttgctgccgccgggcgccccgggacgaggaggtggaggagggagagggcccgcgggcctcgcctccgccctccgccacctcgagctgcggtagcagcgactcatgagagcgcggccggaggacagatttgataatgggctgcattaaaagtaaagaaaacaaaagtccagccattttaatacagacctgaaaatactccagagcctgtcagtacaagtgtgagccattatggagcagaacccactacagtgtcaccatgtccgtcatcttcagcaaagggaacagcagttaatttcagcagtctttccatgacaccatttggaggatcctcaggggtaacgccttttggaggtgcatcttcctcattttcagtggtgccaagttcatatcctgctggtttaacaggtggtgttactatatttgtggccttatatgattatgaagctagaactacagaagacctttcaataagaagggtgaaagatttcaaataattaacaatacggaaggagattggtgggaagcaagatcaatcgctacaggaaagaatggttatatcccgagcaattatgtagcgcctgcagattccattcaggcagaagaatggtattttggcaaaatggggagaaaagatgctgaaagattacttttgaatcctggaaatcaacgaggtattttcttagtaagagagagtgaaacaactaaaggtgcttattccctttctattcgtgattgggatgagataaggggtgacaatgtgaaacactacaaaattaggaaacttgacaatggtggatactatatcacaaccagagcacaatttgatactctgcagaaattggtgaaacactacacagaacatgctgatggtttatgccacaagttgacaactgtgtgtccaactgtgaaacctcagactcaaggtctagcaaaagatgcttgggaaatccctcgagaatctttgcgactagaggttaaactaggacaaggatgtttcggcgaagtgtggatgggaacatggaatggaaccacgaaagtagcaatcaaaacactaaaaccaggtacaatgatgccagaagctttccttcaagattgctcagtttaatgaaaaaattaagacatgataaacttgttccactatatgctgttgtttctgaagaaccaatttacattgtcactgaatttatgtcaaaaggaagcttattagatttccttaaggaaggagatggaaagtatttgaagcttccaaagctggttgatatggctgctcagattgctgatggtatggcatatattgaaagaatgaactatattcaccgagatctccgggctgctaatattcttgtaggagaaaatcttgtgtgcaaaatagcagactttggtttagcaaggttaattgaagacaatgaatacacagcaagacaaggtgcaaaatttccaatcaaatggacagctcctgaagctgcactgtatggtcggtttacaataaagtctgatgtctggtcatttggaattctgcaaacagaactagtaacaaagggccgagtgccatatccaggtatggtgaaccgtgaagtactagaacaagtggagcgaggatacaggatgccgtgccctcagggctgtccagaatccctccatgaattgatgaatctgtgttggaagaaggaccctgatgaaagaccaacatttgaatatattcagtccttcttggaagactacttcactgctacagagccacagtaccagccaggagaaaatttataattcaagtagcctattttatatgcacaaatctgccaaaatataaagaacttgtgtagattttctacaggaatcaaaagaagaaaatcttctttactctgcatgtttttaatggtaaactggaatcccagatatggttgcacaaaaccacttttttttccccaagtattaaactctttatgtaccaatgatgaatttatcagcgtatttcagggtccaaacaaaatagagctaagatactgatgacagtgtgggtgacagcatggtaatgaaggacagtgaggctcctgcttatttataaatcatttcctttctttttttccccaaagtcagaattgctcaaagaaaattatttattgttacagataaaacttgagagataaaaagctataccataataaaatctaaaattaaggaatatcatgggacctaataattccattccagttttttaaagtttcttgcatttattattctcaaaagttttttctaagttaaacagtcagtatgcaatcttaatatatgctttcttttgcatggacatgggccaggtttttcaaaaggaatataaacaggatctcaaacttgattaaatgttagaccacagaagtggaatttgaaagtataatgcagtacattaatttttcatgttcatggaactgaaagaataagaactttttcacttcagtccttttctgaagagtttgacttagaataatgaaggtaactagaaagtgagttaatcttgttttgaggttgcattgattttttaaggcaatatataattgaaactactgtccaatcaaaggcgaaatgttttgatctttagatagcatgcaaagtaagacccagcattttaaaagccctttttaaaaactagacttcgtactgtgagtattgcttatatgtccttatggggatgggtgccacaaatagaaaatatgaccagatcagggacttgaatgcacttttgctcatggtgaatatagatgaacagagaggaaaatgtatttaaaagaaatacgagaaaagaaagtgaaagttttacaagttagagggatggaaggtaatgtttaatgttgatgtcatggagtgacagaatggctttgctggcactcagagctcctcacttagctatattctgagactttgaagagttataaagtataactataaaactaatttttcttacacactaaatgggtatttgttcaaaataatgaagttatggcttcacattcattgcagtgggatatggtttttatgtaaaacatttttagaactccagttttcaaatcatgtttgaatctacattcacttttttttgttttcttttttgagacggagtctcgctctgtcgcccaggctggagtgcagtggcgcgatctcggctcactgcaagctctgcctcccaggttcacaccattctcctgcctcagcctcccgagtagctgggactacaggtgcccaccaccacgcctggctagttttttgtatttttagtagagacgcagtttcaccgtgttagccaggatggtctcgatctcctgaccttgtgatctgcccgcctcggcctcccaaagtgctgggattacaggcgtgagccaccgcgcccagcctacattcacttctaaagtctatgtaatggtggtcatttttttcccttttagaatacattaaatggttgatttggggaggaaaacttattctgaatattaacggtggtgaaaaggggacagtttttaccctaaagtgcaaaagtgaaacatacaaaataagactaatttttaagagtaactcagtaatttcaaaatacagatttgaatagcagcattagtggtttgagtgtctagcaaaggaaaaattgatgaataaaatgaaggtctggtgtatatgttttaaaatactctcatatagtcacactttaaattaagccttatattaggcccctctattttcaggatataattcttaactatcattatttacctgattttaatcatcagattcgaaattctgtgccatggcatatatgttcaaattcaaaccatttttaaaatgtgaagatggacttcatgcaagttggcagtggttctggtactaaaaattgtggttgttttttctgtttacgtaacctgcttagtattgacactctctaccaagagggtcttcctaagaagagtgctgtcattatttcctcttatcaacaacttgtgacatgagattttttaagggctttatgtgaactatgatattgtaatttttctaagcatattcaaaagggtgacaaaattacgtttatgtactaaatctaatcaggaaagtaaggcaggaaaagttgatggtaacattaggttttaactgaatggagcagttccttatataataacaattgtatagtagggataaaacactaactttaatgtgtattcattttaaattgttctgtatttttaaattgccaagaaaaacaactttgtaaatttggagatattttccaacagcttacgtcttcagtgtcttaatgtggaagttaacccttaccaaaaaaggaagttggcaaaaacagccttctagcacacttttttaaatgaataatggtagcctaaacttaatatttttataaagtattgtaatattgttttgtggataattgaaataaaaagttctcattgaatgcacctattaatcgttttagttgctattcatattctcattcgttttttaaaaactgatatttttctgaatttattcttccattgagaaaaaaatgttcagttacttgtaactactgagcagaatttaatcaatcctttattaaattcagaacattattgaa(SEQ ID NO: 671) Metgccctcgccgcccgcggcgccccgagcgctttgtgagcagatgcggagccgagtg NM_001127500NM_008591 gagggcgcgagccagatgcggggcgacagctgacttgctgagaggaggcggggaggcgcggagcgcgcgtgtggtccttgcgccgctgacttctccactggttcctgggcaccgaaagataaacctctcataatgaaggcccccgctgtgcttgcacctggcatcctcgtgctcctgtaaccttggtgcagaggagcaatggggagtgtaaagaggcactagcaaagtccgagatgaatgtgaatatgaagtatcagcttcccaacttcaccgcggaaacacccatccagaatgtcattctacatgagcatcacattttccttggtgccactaactacatttatgttttaaatgaggaagaccttcagaaggttgctgagtacaagactgggcctgtgctggaacacccagattgtttcccatgtcaggactgcagcagcaaagccaatttatcaggaggtgtttggaaagataacatcaacatggctctagttgtcgacacctactatgatgatcaactcattagctgtggcagcgtcaacagagggacctgccagcgacatgtctttccccacaatcatactgctgacatacagtcggaggttcactgcatattctccccacagatagaagagcccagccagtgtcctgactgtgtggtgagcgccctgggagccaaagtcctttcatctgtaaaggaccggttcatcaacttctttgtaggcaataccataaattcttcttatttcccagatcatccattgcattcgatatcagtgagaaggctaaaggaaacgaaagatggttttatgtttttgacggaccagtcctacattgatgttttacctgagttcagagattcttaccccattaagtatgtccatgcctttgaaagcaacaattttatttacttcttgacggtccaaagggaaactctagatgctcagacttttcacacaagaataatcaggttctgttccataaactctggattgcattcctacatggaaatgcctctggagtgtattctcacagaaaagagaaaaaagagatccacaaagaaggaagtgtttaatatacttcaggctgcgtatgtcagcaagcctggggcccagcttgctagacaaataggagccagcctgaatgatgacattcttttcggggtgttcgcacaaagcaagccagattcagccgaaccaatggatcgatctgccatgtgtgcattccctatcaaatatgtcaacgacttcttcaacaagatcgtcaacaaaaacaatgtgagatgtctccagcatttttacggacccaatcatgagcactgctttaataggacacttctgagaaattcatcaggctgtgaagcgcgccgtgatgaatatcgaacagagtttaccacagctttgcagcgcgttgacttattcatgggtcaattcagcgaagtcctcttaacatctatatccaccttcattaaaggagacctcaccatagctaatcttgggacatcagagggtcgcttcatgcaggttgtggtttctcgatcagcaccatcaacccctcatgtgaattttctcctggactcccatccagtgtctccagaagtgattgtggagcatacattaaaccaaaatggctacacactggttatcactgggaagaagatcacgaagatcccattgaatggcttgggctgcagacatttccagtcctgcagtcaatgcctctctgccccaccctttgttcagtgtggctggtgccacgacaaatgtgtgcgatcggaggaatgcctgagcgggacatggactcaacagatctgtctgcctgcaatctacaaggttttcccaaatagtgcaccccttgaaggagggacaaggctgaccatatgtggctgggactttggatttcggaggaataataaatttgatttagagaaaactagagttctccttggaaatgagagctgcaccttgactttaagtgagagcacgatgaatacattgaaatgcacagttggtcctgccatgaataagcatttcaatatgtccataattatttcaaatggccacgggacaacacaatacagtacattctcctatgtggatcctgtaataacaagtatttcgccgaaatacggtcctatggctggtggcactttacttactttaactggaaattacctaaacagtgggaattctagacactttttcaattggtggaaaaacatgtactttaaaaagtgtgtcaaacagtattcttgaatgttataccccagcccaaaccatttcaactgagtttgctgttaaattgaaaattgacttagccaaccgagagacaagcatcttcagttaccgtgaagatcccattgtctatgaaattcatccaaccaaatcttttattagtacttggtggaaagaacctctcaacattgtcagttttctattttgctttgccagtggtgggagcacaataacaggtgttgggaaaaacctgaattcagttagtgtcccgagaatggtcataaatgtgcatgaagcaggaaggaactttacagtggcatgtcaacatcgctctaattcagagataatctgttgtaccactccttccctgcaacagctgaatctgcaactccccctgaaaaccaaagcctttttcatgttagatgggatcctttccaaatactttgatctcatttatgtacataatcctgtgtttaagccttttgaaaagccagtgatgatctcaatgggcaatgaaaatgtactggaaattaagggaaatgatattgaccctgaagcagttaaaggtgaagtgttaaaagttggaaataagagctgtgagaatatacacttttcattctgaagccgttttatgcacggtccccaatgacctgctgaaattgaacagcgagctaaatatagagtggaagcaagcaatttcttcaaccgtcatggaaaagtaatagttcaaccagatcagaatttcacaggattgattgctggtgttgtctcaatatcaacagcactgttattactacttgggtttttcctgtggctgaaaaagagaaagcaaattaaagatctgggcagtgaattagttcgctacgatgcaagagtacacactcctcatttggataggcttgtaagtgcccgaagtgtaagcccaactacagatatggtttcaaatgaatctgtagactaccgagctacttttccagaagatcagtttcctaattcatctcagaacggttcatgccgacaagtgcagtatcctctgacagacatgtcccccatcctaactagtggggactctgatatatccagtccattactgcaattatactgtccacattgacctcagtgctctaaatccagagctggtccaggcagtgcagcatgtagtgattgggcccagtagcctgattgtgcatttcaatgaagtcataggaagagggcattttggttgtgtatatcatgggactttgttggacaattgatggcaagaaaattcactgtgctgtgaaatccttgaacagaatcactgacataggagaagtttcccaatttctgaccgagggaatcatcagggtctccgctggtggtcctaccatacatgaaacatggagatcttcgaaatttcattcgaaatgagactcataatccaactgtaaaagatcttattggattggtcttcaagtagccaaaggcatgaaatatcttgcaagcaaaaagtttgtccacagagacttggctgcaagaaactgtatgctggatgaaaaattcacagtcaaggttgctgattttggtcttgccagagacatgtatgataaagaatactatagtgtacacaacaaaacaggtgcaaagctgccagtgaagtggatggctttggaaagtctgcaaactctaaagtttaccaccaagtcagatgtgtggtcctttggcgtgctcctctgggagctgatgacaagaggagccccaccttatcctgacgtaaacacctttgatataactgtttacttgttgcaagggagaagactcctacaacccgaatactgcccagaccccttatatgaagtaatgctaaaatgctggcaccctaaagccgaaatgcgcccatccttttctgaactggtgtcccggatatcagcgatcttctctactttcattggggagcactatgtccatgtgaacgctacttatgtgaacgtaaaatgtgtcgctccgtatccttctctgttgtcatcagaagataacgctgatgatgaggtggacacacgaccagcctccttctgggacacatcatagtgctagtactatgtcaaagcaacagtccacactttgtccaatggttttttcactgcctgacctttaaaaggccatcgatattctttgctcttgccaaaattgcactattataggacttgtattgttatttaaattactggattctaaggaatttcttatctgacagagcatcagaaccagaggcttggtcccacaggccacggaccaatggcctgcagccgtgacaacactcctgtcatattggagtccaaaacttgaattctgggttgaattttttaaaaatcaggtaccacttgatttcatatgggaaattgaagcaggaaatattgagggcttcttgatcacagaaaactcagaagagatagtaatgctcaggacaggagcggcagccccagaacaggccactcatttagaattctagtgtttcaaaacacttttgtgtgttgtatggtcaataacatttttcattactgatggtgtcattcacccattaggtaaacattcccttttaaatgtttgtttgttttttgagacaggatctcactctgttgccagagcttttagtgcagtggtgtgatcatatctcactgcaacctccacctcccagcctcaagcctcccgaatagctgggactacaggcgcacaccaccatccccggctaatttttgtattttttgtagagacggggttttgccatgttgccaaggctggtttcaaactcctggactcaagaaatccacccacctcagcctcccaaagtgctaggattacaggcatgagccactgcgcccagcccttataaatttttgtatagacattcctttggttggaagaatatttataggcaatacagtcaaagtttcaaaatagcatcacacaaaacatgtttataaatgaacaggatgtaatgtacatagatgacattaagaaaatttgtatgaaataatttagtcatcatgaaatatttagttgtcatataaaaacccactgtttgagaatgatgctactctgatctaatgaatgtgaacatgtagatgttttgtgtgtatttttttaaatgaaaactcaaaataagacaagtaatttgttgataaatatttttaaagataactcagcatgtttgtaaagcaggatacgttttactaaaaggttcattggttccaatcacagctcataggtagagcaaagaaagggtgaatgaattgaaaagattagcctctgtctcggtggcaggttcccacctcgcaagcaattggaaacaaaacttttggggagttttattttgcattagggtgtgttttatgttaagcaaaacatactttagaaacaaatgaaaaaggcaattgaaaatcccagctatttcacctcgatggaatagccaccctgagcagaactttgtgatgcttcattctgtggaattttgtgcttgctactgtatagtgcatgtggtgtaggttactctaactggttttgtcgacgtaaacatttaaagtgttataattttataaaaatgtttatttttaatgatatgagaaaaatttgttaggccacaaaaacactgcactgtgaacattttagaaaaggtatgtcagactgggattaatgacagcatgattttcaatgactgtaaattgcgataaggaaatgtactgattgccaatacaccccaccctcattacatcatcaggacttgaagccaagggttaacccagcaagctacaaagagggtgtgtcacactgaaactcaatagttgagtttggctgttgttgcaggaaaatgattataactaaaagctctctgatagtgcagagacttaccagaagacacaaggaattgtactgaagagctattacaatccaaatattgccgtttcataaatgtaattagtaatactaattcacagagtattgtaaatggtggatgacaaaagaaaatctgctctgtggttaagaaagaactgtctctaccagggtcaagagcatgaacgcatcaatagaaagaactcggggaaacatcccatcaacaggactacacacttgtatatacattcttgagaacactgcaatgtgaaaatcacgtttgctatttataaacttgtccttagattaatgtgtctggacagattgtgggagtaagtgattcttctaagaattagatacttgtcactgcctatacctgcagctgaactgaatggtacttcgtatgttaatagttgttctgataaatcatgcaattaaagtaaagtgatgcaacatcttgtaaaaaaaaaaaaaaaaaaaa (SEQ ID NO: 672) Ppm1gagttgctaaggaaatgactgcccgcagcgcctggccccgccgcgcaggccgggcg NM_177983NM_008014 agttgctaaggaaatgactgcccgcagcgcctggccccgccgcgcaggccgggcggggtctggagcggcgccgtttccgcttccgctccctcacagctcccgtcccgttaccgcctcctggccggcctcgcgcctttcaccggcaccttgcgtcggtcgcgccgcggggcctgctcctgccgcgcgcacccccggggcttcggctccggcacgggtcgcgcccagctttcctgcacctgaggccgccggccagccgccgccatgggtgcctacctctcccagcccaacacggtgaagtgctccggggacggggtcggcgccccgcgcctgccgctgccctacggcttctccgccatgcaaggctggcgcgtctccatggaggatgctcacaactgtattcctgagctggacagtgagacagccatgttttctgtctacgatggacatggaggggaggaagttgccttgtactgtgccaaatatcttcctgatatcatcaaagatcagaaggcctacaaggaaggcaagctacagaaggctttagaagatgccttcttggctattgacgccaaattgaccactgaagaagtcattaaagagctggcacagattgcagggcgacccactgaggatgaagatgaaaaagaaaaagtagctgatgaagatgatgtggacaatgaggaggctgcactgctgcatgaagaggctaccatgactattgaagagctgctgacacgctacgggcagaactgtcacaagggccctccccacagcaaatctggaggtgggacaggcgaggaaccagggtcccagggcctcaatggggaggcaggacctgaggactcaactagggaaactccttcacaagaaaatggccccacagccaaggcctacacaggcttttcctccaactcggaacgtgggactgaggcaggccaagttggtgagcctggcattcccactggtgaggctgggccttcctgctcttcagcctctgacaagctgcctcgagttgctaagtccaagttctttgaggacagtgaggatgagtcagatgaggcggaggtagaagaggaagacagtgaggaatgcagcgaggaagaggatggctacagcagtgaggaggcagagaatgaggaagatgaggatgacaccgaggaggctgaagaggacgatgaagaagaagaagaagagatgatggtgccagggatggaaggcaaagaggagcctggctctgacagtggtacaacagcggtggtggccctgatacgagggaagcagttgattgtagccaacgcaggagactctcgctgtgtggtatctgaggctggcaaagctttagacatgtcctatgatcacaaaccagaggatgaagtagaactagcacgcatcaagaatgctggtggcaaggtcaccatggatgggcgagtcaacgggggcctcaacctctccagagccattggggaccacttctataagagaaacaagaacctgccacctgaggaacagatgattcagcccttcctgacatcaaggtgctgactctcactgacgaccatgaattcatggtcattgcctgtgatggcatctggaatgtgatgagcagccaggaagttgtagatttcattcaatcaaagatcagccagcgtgatgaaaatggggagcttcggttattgtcatccattgtggaagagctgctggatcagtgcctggcaccagacacttctggggttggttcagagtgtgtttaacatgacctgcatcatcatttgcttcaagccccgaaacacagcagagctccagccagagagtggcaagcgaaaactagaggaggtgctctctactgagggggctgaagaaaatggcaacagcgacaagaagaagaaggccaagcgacactagcagtcatccagacccctgcccacctagactgttttctgagccctccggacctgagactgagttttgtctttttcctttagccttagcagtgggtatgaggtgtgcagggggagctgggtggcttcactccgcccattccaaagagggctctccctccacactgcagccgggagcctctgctgtccttcccagccgcctctgctcctcgggctcatcaccggttctgtgcctgtgctctgttgtgttggagggaaggactggcggttctggtttttactctgtgaactttatttaaggacattcttttttattggcggctccatggccctcggccgcttgcacccgctctctgttgtacactttcaatcaacactttttcagactaaaggccaaaacctaa (SEQ ID NO: 673) BlvrbGgcgtggcccttcgagccagctccgccccgttgttctggcttgagtagggcagag NM_000713NM_144923 agcaccgcccaggagccagtgggttcccgcgcgtgccgagactctgaggccttgcacccccacgatcccgtacgatggccgtcaagaagatcgcgatcacggcgccactggccagaccgggacaccagcctggcgcaggcggtgcaagcaggttacgaagtgacagtggtggtgcgggactcctccaggctgccatcagaggggccccggcgggcccacgtggtagtgggagatgttctgcagggagccgatgtggacaagaccgtggctgggcaggacgctgtcatggtgctgctggggacccgcaatgacctcagtcccacgacagtgatgtccgagggcgcccggaacattgtggcagccatgaaggacatggtgtggacaaggtcgtggcctttacctcggctacctgctgtgggaccctaccaaggtgcccgcaggactggaggctgtgactgatgaccacatccggatgcacaaggtgagcgggaatcaggcctgaagtttcgtgggtgtgatgccgccagacataggagaccagccactaactggggcgtacacagtgaccgtggatggacgagggccctcaagggtcatgtcgaaacatgacctgggccatttcatgctgcgctgcctcaccaccgatgagtacgacggacacaggacctagccctcccaccagtaccagtagcactctgtccccattgggagggtggcattctgggacatgaggagcaaaggaagggggcaataaatgttgagccaagagcttcaaattactctagagaaaccgacaaaaaaaaaaaaaaaaaa (SEQ ID NO: 674) Tnk1ggaactcggggtgcggccctcgccggccccgggccagcggccaggtccccgccc NM_ NM_031880tccgcgggatttactcctgtcccgcctcctcggatttagcccaggcagcctgggaggt 001251902tccgcagtcgccgcttccgccttgaccaggtggagctggagacctggtactctagggcctaccctgagctcaccatctgaaggagagtgccatcatccttaggaactccttctccagacatgcttcctgaggctggctccctgtggctactgaagctgctccgggacatccagttggcccagttttactggcccatccttgaggagcttaatgtcactcggccagagcacttcgactttgtaaagcctgaggacctggacggcattggcatgggctggcctgcccagcgcagactgtccgaagctctgaaaaggctacgttctgggcctaagtctaagaactgggtctacaagatccttggaggttttgcccctgagcacaaggagcccaccctgccctcggacagcccacggcacctccctgagccagaggggggcctcaagtgtctgatcccagagggtgctgtttgcagaggggagctgctgggttcaggctgcttcggtgtggtgcaccgagggctgtggacgctgcccagtggcaagagtgtcccagtggctgtcaagtccctccgggtaggtcccgaaggcccgatgggcacagaactgggggacttcctgcgagaggtatcggtcatgatgaacttggagcacccacacgtgctgcgtctgcacggccttgtactgggccagcctctgcagatggtgatggagctggcgccactgggctccctgcacgcgcgcctaacggccccggccccgacacccccgctgctcgtggccctgctctgcctcttcctgcggcagctggcgggagccatggcgtacctgggggcccgcgggctggtgcaccgagacctcgctacgcgcaacctactgctggcgtcgccgcgcaccatcaaggtggctgacttcgggctggtgcggcctctgggcggtgcccggggccgctacgtcatgggcgggccccgccctatcccctacgcctggtgtgccccagagagcctgcgccacggagccttctcgtctgcctcggacgtgtggatgtttggggtgacgctgtgggagatgttctccgggggcgaggaaccctgggccggggtcccaccgtacctcatcctgcagcggctggaggacagagcccggctgcctaggcctcccctctgctccagggccctctactccctcgccttgcgctgctgggccccccaccctgccgaccggcctagcttttcccacctggaggggctgctgcaagaggccgggccttcggaagcatgctgtgtgagggatgtcacagaaccaggcgccctgaggatggagactggtgaccccatcacagtcatcgagggcagctcctctttccacagccccgactccacaatctggaagggccaggatggtcgcaccttcaaagtgggcagcttcccagcctcggcagtgacgctggcagatgcggggggcttgccagccacccgtccagtccacagaggcacccctgcccggggagatcaacacccaggaagcatagatggagacagaaagaaggcaaatctagggatgcgcccccagcacggggccagaggaggaacatgcccctggagaggatgaaaggcatttccaggagtctggagtcagttctgtccctcggtcctcgtcccacagggggtggttcaagcccccctgaaattcgacaagccagagctgtgccccagggacctccaggcctgcctccacgcccacctttatcctctagctctcctcagcccagccagccctctagggagaggcttccctggcccaaaagaaaacccccacacaatcaccccatgggaatgcctggagcccgtaaagccgctgccctctctggaggcctcttgtccgatcctgagttgcagaggaagattatggaggtggagctgagtgtgcatggggtcacccaccaggagtgccagacagcactaggagccactgggggagatgtggtttctgccatccggaacctcaaggtagatcagctcttccacctgagtagccggtccagagctgactgctggcgcatcctggagcattaccagtgggacctctcagctgccagccgctatgtcctggccaggccctgagctcagcttctgcgggcacagacaccagcatgaaaagcctaggcccctgagggcctggccacatgggaccaagcggaaccagaacaaggtcccgacaggggtagacgttccacctggggagatcccacctgccgtaggcacatggaggaggagcccagagttgggcactggcaaatgtctcctccctcccatgctccttggcttctgaaggctgaagctcctttggctgggccaagaaggatctagtctgcccactacattctcaaacaagaggacttggaggaaaagagctgctatacatcatatgcagaggaagcttctacgcgctagagaggatcaaggggccacactggaccatgtgaacagccatcctgaactgccatcagctaccacactggactctgcagggcagccatcctggatgatggaagccaccatattgacttggggtataggcccaaactgccttcgtttggtccagggccatcgtgggtgatgacgattgctctcttgcactcaaggacatttgatgctggtagtatggattatgagatggactagcccctgccccagcccagctctcacattcccctttgttttttcccataccaactgcttctaccctcccctattacatacttctttcaatgtccaaaaagttacaaagtttatatgaatgtaacatataaaaaaa (SEQ ID NO: 675) Prkab2actgggcggactccgcgccgccggccttgtagccattttaggaggaatcgctggtcg NM_005399NM_182997 ccagcgaggggtgcggcttcaatttcaataactttattggtggcctgatctgcagaacagccatcacatatgtggcccttggaggttgggagcgcatcgcccgaggtggtccccgacgagctgcagccatgggaaacaccaccagcgaccgggtgtccggggagcgccacggcgccaaggctgcacgctccgagggcgcaggcggccatgccccggggaaggagcacaagatcatggtggggagtacggacgaccccagcgtgttcagcctccctgactccaagctccctggggacaaagagtttgtatcatggcagcaggatttggaggactccgtaaagcccacacagcaggcccggcccactgttatccgctggtctgaaggaggcaaggaggtcttcatctctgggtccttcaacaattggagcaccaagattccactgattaagagccataatgactttgttgccatcctggacctccctgagggagagcaccaatacaagttctttgtggatggacagtgggttcatgatccatcagagcctgtggttaccagtcagcttggcacaattaacaatttgatccatgtcaagaaatctgattttgaggtgttcgatgctttaaagttagattctatggaaagttctpgacatcttgtagagacctttccagctcacccccagggccttatggtcaagaaatgtatgcgtttcgatctgaggaaagattcaaatccccacccatccttcctcctcatctacttcaagttattcttaacaaagacactaatatttcttgtgacccagccttactccctgagcccaaccatgttatgctgaaccatctctatgcattgtccattaaggacagtgtgatggtccttagcgcaacccatcgctacaagaagaagtatgttactactctgctatacaagcccatttgaagggatcccttcttgcctctaaggattcaggagaagcatctcccttgcatttctggactgaaccagtcttacctgagactggaaggctgatttgctttgaggctgatatgtgtgtttcagagcctctgagtaggatgctctgcttttgcatttgattgcagatgagagctttatgagttcacggaatttattttaagaaaaaaaaatatacatatgagaagaaggtaaatggaagcctcctagccccagctagaagtaagtttctgcctgtgggttttcaccaagacctgtttgggggcgctgcaggaataactatataggaagatttttcctaaaatgaaagaacagcaaactcttaggatccttgttgggtggagattctatcactgctaccttggctctccaaggaatgggcttgtgctagaccgctgccctacttaacagctgcctcattgcaagggcagtttttcttgcatgggttctctatattcccagagtatgtggcacaatctgtgttgtttatatgataccagatgccccacaagaacccttattcctctcatttcacattcttcctttaatagcctccttcagatcccatacctgacccctctctaacacaaaacttattgggtaagtgactttgaaaagttttgtggcacctgacccaccccagacactagggctatcagaaggtctcctttttagcccagcacaggcccaggccactttgtcgtgtttgttttaacttctaaagaaaattttgtttcagcattataagttaaggcagaatgcagaacacctacatttttgttttagtttggtgccaaggctcaggctgtttttggcaaattcccgaaagttttcccactttgcctggccctgcactgtcttttctttctatgtaaacagttctgtaggcaggagtggaacccgggagtattttcatgtctttcatccttgaaagatttttatgtgcagcattttttttttaattaaaaaatgccttttcattggtcttaagagaccgcattggagaatttcaggcttttgataaatgcttcttcaaagagattttcttctctagtctagccttccacattcttagattaatatggccaaccctgtacacatcactacactaaacactgctctagataaactgctcaagttcatttaactcatttgatgcacctaaaggggttcctcattttaaagatttgttaggccaagaagcaagagagtattcctagtattcccaaccatgaaaagtatcattctttgcaccaaatgttaacaaaatcattttgttctcctgcctcttctttttaaaggtgtttgatgattaagtggggtcactgaattccatttgtggactgaaaagtattcaatccacttttggggttcagagataaaacattttttcccaagtagctggggctcttccattttgcagatttttgtcaaataatcaacactaaaggaggctaaactgttttatgaatgagagactccctgactgctcagatgaccctagccacactgaaagggcacctacaggtcagtttagctacctcctgtctttcccatgcaaagctgataacacagttgtctttggacttgtagacctcttggattccaggtgtgatggagtaaagtgtgggattgttgttttgctgggatggccaccttctgcagcaaaaggcttttgtggagaaccttttatgttcccaaccactttttgaatggtgtgccatttaaaaatccaggccagatcctattataaccaactctcaggatttacagccttcagttgtactagaattttgtttaatccaatactcattaaataagtgggccacttaggaagattcaaaatcttggttattacatgaagtttgttatatttcttgtcaacagtattgaaatgtaatatgtatgtgttcatgtatgaaaatttttactccacacaggtgtttcagtagagtggggcaggaaaagagatctcttcgatttctttcaggcctgaggcttttgtgaaatgcgtcagccccctgtgacagtaggttttgatgctagtgatcttcagatctttctctctggaaatgtgcagagagtgtcagtttcccaagttctgaggtaactctcagcccagatgtgaaatgggagcctaccagctggtatagaagggaatgggtaggaggcactgggtgctgactcattcagcactgtcccttttctatactgctgatacatcccatggttctgagaagccttatctcagtctatttggaagagagggaggaagagaaggaagtaacccaaagtactactcatttatcattgtatattgattagttaaagggataattaatttaatgctgaggagagtttgacagattttgaaaatgagtaaaggcaaaaaaaatttttttagcctttattttgcttttgggaattttacagagtcaaagtaggcagaataagaaaatagttcttcaggagggccgacctttaaagaacttcaacatagtttcggaattgtggggaagagaagagtgactgagctgagaagtaataatagaataaagggttgagtaacttacaactgaaaatgatctcttttaaaaagaaattaaatcagacaccacatggtggtgtccttggatctcactgtacagaattagcagtgtataaccatcttctcttttcatcttgttccaattctctcctctttcctttccattctgctttaagctcatgtgtcaggcagactttaccagagtgtcagacattacctaaaacacatacgttagccatgctgctggtatggagattattccacaccatgattattagcctcctttaagctgaatgggatttaaccattctaggcaacacccctgaagggcatacctaacctcaatagtgttggcttttaaaacgtatgtttgtatggtagagaaactttgtaaaagaagatttccaagagaagtttgtgaggatcctacaaacccaggcccactcactttgctctttattctttctagtatcttgtagatctaatgggtctgggataaaaactttgaaaagtgtcaatattccatgtatgctgctgaaatgaagttaagtttggaaagaagtgatacctctagactgggtttatattaatctgggatataaatgaagaagacatactaatagaactccttgcttttaattggggaaatagggctttaataattttgacctcaactaaaaatgatatgcaatagtctctgtgtgtgtttgaaatacattgtgttctcagagatttctacattctcacgttctagtgatttggggcatgggcttaatagcagatgtacagtgtattcctgcattattgtgattccccttaaagcccagttcttgctgtcttctaccaggggctgctgactccagttacccatggaatgcaggacctgggaggggtagccattagggtctttcaaaactctttggatctaagcatttgtcactccttaagtgccaatcacaattggatatggaaggactgtgatttctgcaatgaacccaaacttttagagtaaaaagccaaatttaaattataagaaagaagggaaaaaagagaaaaactcaagtctattacttgtagagtccaattcttagcaatggaatcgctctaggattctagtttgggctttgtctggatttgcttttctcagttgtgctttgaagtgaataagctttgttacaaattaattttttattagttccaatattagttggagttaacttgaattgattgtatgtagcacagcacttttgcagtaagattggtgtgaaatactaaacactatggattttgtaggtgtcaggttaaatggtcaagggatacctctcattaagtcatatattaggtattgatgatcttacttcttttctgttcccagtacaaaacacttacctaacccagcttgtggttttaggacagccaaagctcactgttgttggttagtcctaatcactacacgggtctcataaatgagacttgtttgaattttggtacattggagcatgttggttggtattacacggcagcatttcgaatgagtgcagctctgtgtctgtcagaaaggagagataagactactttgaagggaattaaatatgtgagtcctctttttaatggtgctttttgtaacctttaatgctgaggtacagagctgctttttcaatatttcataaaggagtggcagacaagagtggattttaaagctgttcttcaaacgtaatttgtcactggactctgacacacctggaaattatatgatatgatacatacagaaatgttgtgggttttttccataaaactttaataaaagtattatacagcaataaaaaaaaaaaaaaa(SEQ ID NO: 676) Trpm7gcgcgctcacgtggtccgtccccagccccgtcgccggcggaggcgggcgcggg NM_017672NM_021450 gcgccgctcacgtggtccgtccccagccccgtcgccggcggaggcgggcgcgggcgcgtccctgtggccagtcacccggaggagttggtcgcacaattatgaaagactcggcttctgctgctagcgccggagctgagttagttctgagaaggtttccctgggcgttccttgtccggcggcctctgctgccgcctccggagacgcttcccgatagatggctacttggccgcggaggaggaggaggtggagttgctgcccttccggagtccgccccgtgaggagaatgtcccagaaatcctggatagaaagcactttgaccaagagggaatgtgtatatattataccaagttccaaggaccctcacagatgccttccaggatgtcaaatttgtcagcaactcgtcaggtgtttttgtggtcgcttggtcaagcaacatgcttgttttactgcaagtcttgccatgaaatactcagatgtgaaattgggtgaccattttaatcaggcaatagaagaatggtctgtggaaaagcatttcagaacagagcccaacggatgcttatggagtcataaatatcaagggggttctcattcctacagagctaagtatgtgaggctatcatatgacaccaaacctgaagtcattctgcaacttctgcttaaagaatggcaaatggagttacccaaacttgttatctctgtacatgggggcatgcagaaatttgagcttcacccacgaatcaagcagttgcttggaaaaggtcttattaaagctgcagttacaactggagcctggattttaactggaggagtaaacacaggtgtggcaaaacatgaggagatgccctcaaagaacatgcttccagatcatctcgaaagatttgcactatcggaatagctccatggggagtgattgaaaacagaaatgatcttgttgggagagatgtggttgctccttatcaaaccttattgaaccccctgagcaaattgaatgttttgaataatctgcattcccatttcatattggtggatgatggcactgttggaaagtatggggcggaagtcagactgagaagagaacttgaaaaaactattaatcagcaaagaattcatgctaggattggccagggtgtccctgtggtggcacttatatttgagggtgggccaaatgttatcctcacagttcttgaataccttcaggaaagcccccctgttccagtagttgtgtgtgaaggaacaggcagagctgcagatctgctagcgtatattcataaacaaacagaagaaggagggaatcttcctgatgcagcagagcccgatattatttccactatcaaaaaaacatttaactttggccagaatgaagcacttcatttatttcaaacactgatggagtgcatgaaaagaaaggagcttatcactgttttccatattgggtcagatgaacatcaagatatagatgtagcaatacttactgcactgctaaaaggtactaatgcatctgcatttgaccagcttatccttacattggcatgggatagagttgacattgccaaaaatcatgtatttgtttatggacagcagtggctggttggatccttggaacaagctatgcttgatgctcttgtaatggatagagttgcatttgtaaaacttcttattgaaaatggagtaagcatgcataaattccttaccattccgagactggaagaactttacaacactaaacaaggtccaactaatccaatgctgtttcatcttgttcgagacgtcaaacagggaaatcttcctccaggatataagatcactctgattgatataggacttgttattgaatatctcatgggaggaacctacagatgcacctatactaggaaacgttttcgattaatatataatagtcttggtggaaataatcggaggtctggccgaaatacctccagcagcactcctcagttgcgaaagagtcatgaatcttttggcaatagggcagataaaaaggaaaaaatgaggcataaccatttcattaagacagcacagccctaccgaccaaagattgatacagttatggaagaaggaaagaagaaaagaaccaaagatgaaattgtagacattgatgatccagaaaccaagcgctttccttatccacttaatgaacttttaatttgggcttgccttatgaagaggcaggtcatggcccgttttcatggcaacatggtgaagaatcaatggctaaagcattagttgcctgtaagatctatcgttcaatggcatatgaagcaaagcagagtgacctggtagatgatacttcagaagaactaaaacagtattccaatgattttggtcagttggccgttgaattattagaacagtccttcagacaagatgaaaccatggctatgaaaagctcacttatgaactgaagaactggagtaattcaacagccttaagttagcagtttcttcaagacttagaccttttgtagctcacacctgtacacaaatgttgttatctgatatgtggatgggaaggctgaatatgaggaaaaattcctggtacaaggtcatactaagcattttagttccacctgccatattgctgttagagtataaaactaaggctgaaatgtcccatatcccacaatctcaagatgctcatcagatgacaatggatgacagcgaaaacaactttcagaacataacagaagagatccccatggaagtgtttttaagaagtacggattttggatagtaatgaaggaaagaatgagatggagatacaaatgaaatcaaaaaagcttccaattacgcgaaagttttatgccttttatcatgcaccaattgtaaaattctggtttaacacgttggcatatttaggatttctgatgctttatacatttgtggttcttgtacaaatggaacagttaccttcagttcaagaatggattgttattgcttatatttttacttatgccattgagaaagtccgtgagatctttatgtctgaagctgggaaagtaaaccagaagattaaagtatggtttagtgattacttcaacatcagtgatacaattgccataatttctttcttcattggatttggactaagatttggagcaaaatggaactttgcaaatgcatatgataatcatgtttttgtggctggaagattaatttactgtcttaacataatattttggtatgtgcgtttgctagattttctagctgtaaatcaacaggcaggaccttatgtaatgatgattggaaaaatggtggccaatatgttctacattgtagtgattatggctcttgtaaacttagttttggtgttcccagaaaggcaatactttatcctcatgaagcaccatcttggactcttgctaaagatatagtttttcacccatactggatgatttttggtgaagtttatgcatacgaaattgatgtgtgtgcaaatgattctgttatccctcaaatctgtggtcctgggacgtggttgactccatttcttcaagcagtctacctctttgtacagtatatcattatggttaatcttcttattgcatttttcaacaatgtgtatttacaagtgaaggcaatttccaatattgtatggaagtaccagcgttatcattttattatggcttatcatgagaaaccagttctgcctcctccacttatcattcttagccatatagtttctctgttttgctgcatatgtaagagaagaaagaaagataagacttccgatggaccaaaacttttcttaacagaagaagatcaaaagaaacttcatgattttgaagagcagtgtgttgaaatgtatttcaatgaaaaagatgacaaatttcattctgggagtgaagagagaattcgtgtcacttttgaaagagtggaacagatgtgcattcagattaaagaagttggagatcgtgtcaactacataaaaagatcattacaatcattagattctcaaattggccatttgcaagatctttcagccctgacggtagatacattaaaaacactcactgcccagaaagcgtcggaagctagcaaagttcataatgaaatcacacgagaactgagcatttccaaacacttggctcaaaaccttattgatgatggtccttttaagaccttctgtatggaataagcatggtgttgtaaatacacttagctcctctcttcctcaaggtgatcttgaaagtaataatccttttcattgtaatattttaatgaaagatgacaaagatccccagtgtaatatatttggtcaagacttacctgcagtaccccagagaaaagaatttaattttccagaggctggttcctcttctggtgccttattcccaagtgctgtttcccctccagaactgcgacagagactacatggggtagaactcttaaaaatatttaataaaaatcaaaaattaggcagttcatctactagcataccacatctgtcatccccaccaaccaaattttttgttagtacaccatctcagccaagttgcaaaagccacttggaaactggaaccaaagatcaagaaactgtttgctctaaagctacagaaggagataatacagaatttggagcatttgtaggacacagagatagcatggatttacagaggtttaaagaaacatcaaacaagataaaaatactatccaataacaatacttctgaaaacactttgaaacgagtgagttctcttgctggatttactgactgtcacagaacttccattcctgttcattcaaaacaagcagaaaaaatcagtagaaggccatctaccgaagacactcatgaagtagattccaaagcagctttaataccggattggttacaagatagaccatcaaacagagaaatgccatctgaagaaggaacattaaatggtctcacttctccatttaagccagctatggatacaaattactattattcagctgtggaaagaaataacttgatgaggttatcacagagcattccatttacacctgtgcctccaagaggggagcctgtcacagtgtatcgtttggaagagagttcacccaacatactaaataacagcatgtcttcttggtcacaactaggcctctgtgccaaaatagagtttttaagcaaagaggagatgggaggaggtttacgaagagctgtcaaagtacagtgtacctggtcagaacatgatatcctcaaatcagggcatctttatattatcaaatcttttcttccagaggtggttaatacatggtcaagtatttacaaagaagatacagttctgcatctctgtctgagagaaattcaacaacagagagcagcacaaaagcttacgtttgcctttaatcaaatgaaacccaaatccataccatattctccaaggttccttgaagttttcctgctgtattgccattcagcaggacagtggtttgctgtggaagaatgtatgactggagaatttagaaaatacaacaataataatggagatgagattattccaactaatactctggaagagatcatgctagcctttagccactggacttacgaatatacaagaggggagttactggtacttgatttgcaaggtgaggtgaaaatttgactgacccatctgtgataaaagcagaagaaaagagatcctgtgatatggtttttggcccagcaaatctaggagaagatgcaattaaaaacttcagagcaaaacatcactgtaattcttgctgtagaaagcttaaacttccagatctgaagaggaatgattatacgcctgataaaattatatttcctcaggatgagccttcagatttgaatcttcagcctggaaattccaccaaagaatcagaatcaactaattctgttcgtctgatgttataatattaatattaagaatcattggtttIgcctgcacctcacagaaatgaactgtgtcacttttccctcgggaggaaattgtttggtaatatagaaaggtgtatgcaagttgaatttgctgactccagcacagttaaaaggtcaatattcttttgacctgattaatcagtcagaaagtccctataggatttgagctggcagctgagaaattttaaaggtaattgataattagtatttataaattttaaagggctctttgtatagcagaggatctcatttgactttgttttgatgagggtgatgctctacttatgtggtacaataccattaaccaaaggtaggtgtccatgcagattttattggcagctgttttattgccattcaactagggaaatgaagaaatcacgcagccttttggttaaatggcagtcaaaattttcctcagtgtatttagtgtgttcagtgatgatatcactggttcccattctttgtttgcttgttggccacgggaagggaaatgacttgttctaattctaggttcacagaggtatgagaagcctgaactgaagaccattttcaagagggacggtatttatgaatcagggttaggctccatatttaaagatagagccagtttttttttttaaatagaacccaaattgtgtaaaaatgttaattgggttttttaaacattgttttatcaagtcactgttaagtagaagaaagccatggtaaactgatacataacctaaattataaaagcagaaacctaactcactcgtcaagggttagttaccttttgaggaaagttaaagtacttttttccctatctgtatctatagcaacaacccagaacttacaaacttcgccaaagatttgattgattgttatatcaaatcagaatgtaaacatgaactcttgcatatatttaaaattgtgttggaacatttgaacatgaatgctgtttgtggtacttaagaaattaattcagttggattatcattatgtgatactggcagattgcagtgcaaccttatgccaataaaatgtaatttaacagccccagatattgttgaatattcaacaataacaagaaaagcttttcatctaagttttatgctttaattttttttctattttttctttttcaagtaccttggtactaattttaatttttatttggaagggagcagtataaagcttatttgtatttagtagtgtatctcatagatacagacaaggcaagagatgataagctgtttaaatagtgtaaatattgattgggggtggggagaaagaaaaagtgtattacttaaagatactatatacgttttgtatatcattaaatctttaaaagaaatgaaataaatttattgtttacagatgtttagtgagtttaatcattctgaaaaattatctgacattttcagggtgtcaatttgagtatcagtttttttaaatgaaccatttgtatacctgtgcttttgatctcctgtcctgtacaatgtttaaattaatactgatttcttactgtcttcttagaaatctgttttttgttaggccaaaaaagggcaatatgggctgtctgttgatttttaattttatattgattattttcacaggattataatagtagctatacttttttttttttttttttttttgagacggagtctcgctctgttgcttgggctggagtgcagtggtgcgatctcagctcaccacaaccgccgccttccgggtttaagtgattctcctgcctcagcctcccgagtagctgggactacaggcacacgccaccatgcccagctaattatatatttttagtagagacagggtttcactatgttggccagtgtggtcacaaactcctgaccttgtgagccaccgcacctgttctgctaacacttatttagtgcctactgtgtaccagacattactctaagtatttcacatatattaacctacttaatccttataacaatgttataaagaaataggtgttattatcctgttttgcagatttgaaagtcaaggtgctagagaggtaaagtaacgtccataagattcttacgtttatttaataataagtagcaacggtaggatttgaacccaggctggctgcctttcatctatactgtttttgttttgttttgttttgttttgttttgttttgtttgtcttggtggggcatggtggctcatgcctgtaatcccagcacttcgggaggccaaggcaggtggatcacttgggctcaggagtttgagaccagcctgggcaacatggcaaaatcctatctctgctaaaaaaaaaaatacaaaaattaggccaggtgcagtggctcatgcctgtaatcccagcactttgggaggccaaggtgggcggatcacaaggtcaggagttcgagaccagcctgaccaacatagtgaaaccccgtctctactaaaaatacaaaaaattagctgggcatggcggtgagtgcctgtaatcccagctactcaggagtctgaggcaggagaattgcttgaacctgggaggtggaggttgcagtgagctgagatcgtgccattgcgctccagcctgggcaacagtgcgagactccgtcaaaaaaaaaaaaataactggatgtgatggtgtgcacctgtagttccagctacttgggagactgaggtgggaggatcacttgagcctgggagactgaggcagcagtgagctgagatcatgccactgctttccaacctgggcaacagagtgagatcctgtctcagaaagaaaaaaaaaaaaaagacaacctcttgctctgttgcccaggctggagtgtagtagcgtgatcatagctcactgcagccgtaaactcctgggctcaagcaatcctcctgccactgcctcttgattaggtggaaccacaggcatgcaccaccacacgtacctaattttatatatatatttttttatttttcatttttattttttttttgtttttttgagttgaagtctcactctgttgcccaggccggagtacagtggcacaatcttggctcactgcaacctctgcctcccaagatcaagcaattctcgtgcttcagcctccaaagtagctgagattacaggtacccaccattatgcctggctgatttttgtatttttcgtagagacaaggtttcaccttgttggccaggctgatctcaaactcctgacctcaagtgatccacctcccccggctacccaaagtactgggattataggtgtgagccaccatgcctgggtaacacccaactaattttaaatatatattttgtagagatggggtctagccttgttgcccacgctggtctcaaattcctgggctcaagtgatcctctcgcctgagcttcccaaagtggtagaattgcaggcatgaattgctgcacccagcctcatctgtgctgtgaattatgtgctgtattgactctcaagcatgatgaccattggtggtttctgtaccatttcctgttactttactgaaacacacctactccattaacttcttgggttaagtctagaaagtaacagtttacttgtaaaccacatttcttatccccaataagtattttataagattattaaagttcattattactaccctatgatgtgaaagtgtcatttgcttaatctttttaaattttattctcaacctcatcttactgaagagaataaaactcttttaccatattcttaaaatgtggaattctcggccaggtgcagtggctcacgcctgtaattccatcactttgggaggccaaggtgggjggatcatctgaggtcaggagttcaagaccagcctggccaacatggtgagtaccccgtctctactaaaaatacaaaaattatctgggtgtggtggcgcgtgcctgtaggcccagctactcaggaggctgaggcaggagaattgatgaacccaagaggtggaggttgcagtgagcctagattgctgccactgcactccagcctgggtgacagcagaactctgtctcaaaaaaaacatgtggaattcttttctgcaaatgttctctaatagtataccttcttcagtctctcgatatatgtatgctattattttacaagtaatacatgttgattgtattggaaattatagaaaagattatattggattgtttagaaaatatttttaaatgtgaagaaaaatataaaaattactcccttgttccactttccccactctcaagttagactatgttgttttcatagttagtttgctagcagtctaccccactagattatatgcttcacagagggaagggaccctcaagaatcactggattgagtagcacccaataccttgcttgctgcctggtttgtgatgggcatactgtaagaaaaaaaaatctgaatgacaaaatgtttttccataataccagacttcctcttgaagagatgggtcgtaatgttgtagtcttacatgcttacgtagacaatcaaagcaagaatactcaataaatggctatttaccacttgaaagaaa (SEQ ID NO: 677) Ppp3ccaaggcggaagggtggggagggcggcgctcggggcgggaggcccggccgggtc NM_001243974NM_008915 cgctaggacagcggggccgctgggaagttgtgagagcggcgctcgggggcgcgcttgcgtgcacgagggcccgggccgcgagcagccgcggccgtcccggtcgccacccttagcagcggtcgcggtcggtgccgaagcggtgttccccgccttagccgctggcgcctcccaagagagcggccggtgggccctcgtcctgtcagtggcgtcggaggccggcgctgcggtggccgcgcccttctggtgctcggacaccgctgaggagccggggccgggcacggctggctgacggctccgggcagctaaggctgcccgaggagaaggcggcggccgcggcgtaggcgcacgtccggcgggctcctggagcctggaggaggccgaggggaccatgtccgggaggcgcttccacctctccaccaccgaccgcgtcatcaaagctgtcccctttcctccaacccaacggcttactttcaaggaagtatttgagaatgggaaacctaaagttgatgttttaaaaaaccatttggtaaaggaaggacgactggaagaggaagtagccttaaagataatcaatgatggggagccatcctgaggcaagagaagactatgatagaagtagatgctccaatcacagtatgtggtgatattcatggacaattctttgacctaatgaagttatttgaagttggaggatcacctagtaacacacgctacctctttctgggtgactatgtggacagaggctattcagtatagagtgtgtgctgtattatggagtttaaagattaatcatcccaaaacattgtttctgcttcggggaaatcatgaatgcaggcatcttacagactatttcaccttcaaacaggaatgtcgaatcaaatattcggaacaggtgtatgatgcctgtatggagacatttgactgtcttcctcttgctgccctcttaaaccagcagtttctctgtgtacatggaggaatgtcacctgaaattacttctttagatgacattaggaaattagacaggtttacggaacctcccgcctttggacctgtgtgtgacctgctttggtctgatccctcagaggattatggcaatgagaagaccttggagcactatacccacaacactgtccgagggtgctcttatttctacagttaccctgcagtttgtgaatttttgcagaacaataatttactatcaattatcagagcccatgaagcccaagatgctgggtatcgaatgtacaggaagagccaagccacaggctttccatcacttattacaattttctctgcccccaattacctagatgtctataacaataaagctgctgtgttgaaatatgaaaacaatgtcatgaatatcaggcagtttaactgttctccacacccctactggcttccaaactttatggatgttttcacatggtctttgccttttgttggggaaaaagtcacagagatgctggtaaatgtgctcaacatatgctctgatgacgaactgatttctgatgatgaagcagaagatcactacattccaagctatcagaaaggaagcactacagttcgtaaggagatcatcaggaataagatcagagccattgggaagatggcacgggtcttttcaattcttcggcaagaaagtgagagtgtgctgactctcaagggcctgactcccacaggcacactccctctgggcgtcctctcaggaggcaagcagactatcgagacagccacagtagaagcggtagaggcccgggaagccatcagagggttctcgcttcagcacaagatccggagttttgaagaagcgcgaggtctggaccgaattaatgagcgaatgccaccccgaaaggatagcatacacgctggtgggccaatgaaatctgtaacctcagcacactcacatgctgcgcacaggagcgaccaagggaagaaagcccattcatgacttagagtcctgccgtggctcaggtggatctaaaactcaagaacaaattctatttatttattattggaaaatgaaaagcaactcaaaacaacttcaacgtggaggtgcatttataattcagtctgcatttattctgtaaaaaggtggctgttttataaattcttttaatttatgttcaatatatataaaaagtgcatctgttttgtttttcccttttttctccataattttaagaaatgaatctgattgttgtcaacacatttgtgaagtcttgtgctataaaggggaacttcccctaataaaagggccttggaaacctcaaacctgggtttctgacttgaaaaaaaaaaaaaaa (SEQ ID NO: 678)

In some aspects, the nucleic acids of the compositions encode the shRNAsequences targeting the sequences provided in Table 2. Table 2 furtherdemonstrates enrichment in tumor versus spleen for the selected shRNAbased on deep sequencing

TABLE 2 Mouse Mouse SEQ Human Gene Gene ID Enrich Gene Human Symbol IDshRNA Clone ID shRNA Target Sequence NO: Fold Symbol Gene ID Akap8l54194 ND000290 CGAAACCGCAGGCTTATGATG 1 0.5 AKAP8L 26993 Akap8l 54194ND000285 CAGACTGCTCAGACAACAGTG 2 0.7 AKAP8L 26993 Akap8l 54194TRCN0000288034 CCACAAGGAACACTTCAAATA 3 1.0 AKAP8L 26993 Akap8l 54194ND000291 AGACCTCTACCGGTCAAGCTA 4 1.1 AKAP8L 26993 Akap8l 54194 ND000286ATAGAGGCTACGAGAACTATG 5 1.4 AKAP8L 26993 Akap8l 54194 TRCN0000288033CCAGAACATCATACCCGAGTA 6 1.6 AKAP8L 26993 Akap8l 54194 ND000289TTAGATATGATGCCGCACTTG 7 1.7 AKAP8L 26993 Akap8l 54194 TRCN0000088483CCCACCTGTGATTATGGATAT 8 1.8 AKAP8L 26993 Akap8l 54194 ND000288GGCGAGAATCCTTTCACTGAC 9 1.9 AKAP8L 26993 Akap8l 54194 TRCN0000088486CGAGAACTATGGTTATGGCTA 10 2.1 AKAP8L 26993 Akap8l 54194 ND000292CAAATACCGGACCTTCTATGA 11 2.8 AKAP8L 26993 Akap8l 54194 TRCN0000307538GATATCTGAAGGGCGAGAATC 12 3.8 AKAP8L 26993 Akap8l 54194 TRCN0000307539ACCGGTCAAGCTATGACTATG 13 4.4 AKAP8L 26993 Akap8l 54194 ND000287TTGGATTTGGCAATGGCATGA 14 7.1 AKAP8L 26993 Akap8l 54194 TRCN0000088487 CCGAAACCACTTTGCAGTCTA 15 11.8 AKAP8L 26993 Alk 11682 TRCN0000361004ACCTAGAGGAGAATCACTTTA 16 0.2 ALK 238 Alk 11682 TRCN0000023725GCCTTCATGGAAGGGATATTT 17 0.4 ALK 238 Alk 11682 TRCN0000361067CGGGCCTGTATACCGGATAAT 18 0.7 ALK 238 Alk 11682 TRCN0000361003GTGGAGCCACCTACGTGTTTA 19 0.9 ALK 238 Alk 11682 ND000299GGAATCTGACCTGGACGATGA 20 1.0 ALK 238 Alk 11682 ND000293CTTCGTTGTACCCTCGCTCTT 21 1.1 ALK 238 Alk 11682 ND000298GAAGGGATATTTACCTCTAAA 22 1.3 ALK 238 Alk 11682 TRCN0000023728CCGGGATATTGCTGCTAGAAA 23 1.7 ALK 238 Alk 11682 TRCN0000023724GCATCGCATTGGAGGCTATAA 24 2.1 ALK 238 Alk 11682 ND000297GGGCCTGTATACCGGATAATG 25 2.4 ALK 238 Alk 11682 TRCN0000023726CGGAGGATATATAGGTGGCAA 26 2.9 ALK 238 Alk 11682 ND000300ATCGAATACGGTCCAGTAGTA 27 3.4 ALK 238 Alk 11682 ND000296TGCTTCCGCGTAGTCAGAAAT 28 3.8 ALK 238 Alk 11682 ND000294CCTGCGGCAATGTCAACTATG 29 9.4 ALK 238 Alk 11682 TRCN0000023727CCCGAACGTCAACTATGGTTA 30 9.5 ALK 233 Alk 11682 ND000295GGCGAGGAGACGATTCTTGAA 31 13.5 ALK 238 Arhgap5 11855 TRCN0000321111TGGTACATATCCTCGTAAATT 32 0.5 ARHGAP5 394 Arhgap5 11855 TRCN0000360350ATTGCAATCAGTATATCATTC 33 0.8 ARHGAP5 394 Arhgap5 11855 TRCN0000360421GATCATGAACGTAACCATAAA 34 1.2 ARHGAP5 394 Arhgap5 11855 TRCN0000360349TGATAATAGCAGCAACTAAAT 35 1.3 ARHGAP5 394 Arhgap5 11855 TRCN0000321112AGCATGACTGGAGAGGTTTAA 36 1.4 ARHGAP5 394 Arhgap5 11855 TRCN0000321110TGATAGTCAGAATCGAATTAT 37 1.4 ARHGAP5 394 Arhgap5 11855 TRCN0000321109GAACTGGTTCATGGGTATATA 38 1.5 ARHGAPS 394 Arhgap5 11855 TRCN0000012706GCAAGCTCTAAGAGGAGTATT 39 3.6 ARHGAPS 394 Arhgap5 11855 TRCN0000012707CCTGATCCTTTGATTCCATAT 40 6.0 ARHGAPS 394 Arhgap5 11855 TRCN0000321181ACAGATCCTCTTGGTATTATA 41 8.3 ARHGAP5 394 Arhgap5 11855 TRCN0000012703GCACGATTTAATGTCAACATT 42 15.7 ARHGAP5 394 Blvrb 233016 ND000310CTCAGTCCCACTACAGTAATG 43 0.8 BLVRB 645 Blvrb 233016 ND000308TGACCACATCCGGATGCATAA 44 1.0 BLVRB 645 Blvrb 233016 ND000306GCCTCACCACCAATGAGTATG 45 1.2 BLVRB 645 Blvrb 233016 ND000309TGAGAAATGACACAAATAGAG 46 1.2 BLVRB 645 Blvrb 233016 ND000303TGCAAGAGTCAGGGCTGAAAT 47 1.3 BLVRB 645 Blvrb 233016 ND000301GGAAGCTGTCATCGTGCTACT 48 1.5 BLVRB 645 Blvrb 233016 ND000304GCATAAGATTCTGCAAGAGTC 49 1.9 BLVRB 645 Blvrb 233016 TRCN0000042385CCTCAGTCCCACTACAGTAAT 50 2.2 BLVRB 645 Blvrb 233016 ND000302TCGAGGGTCATATCCAAGCAT 51 2.4 BLVRB 645 Blvrb 233016 TRCN0000324726GAACATCGTGACAGCCATGAA 52 3.0 BLVRB 645 Blvrb 233016 TRCN0000042384CCAATGAGTATGACGGACACA 53 3.1 BLVRB 645 Blvrb 233016 ND000307GAGGGTCATGCATCCTGAGAA 54 3.1 BLVRB 645 Blvrb 233016 ND000305TAGGAGACCAACCACTAACTG 55 5.3 BLVRB 645 Blvrb 233016 TRCN0000324662GCTGAAATACGTGGCAGTGAT 56 5.3 BLVRB 645 Blvrb 233016 TRCN0000042386CGGATGCATAAGATTCTGCAA 57 8.0 BLVRB 645 Cblb 208650 ND000027TCTACATCGATAGTCTCATGA 58 0.7 CBLB 868 Cblb 208650 TRCN0000244603CTACACCTCACGATCATATAA 59 0.9 CBLB 868 Cblb 208650 TRCN0000244605TGAGCGAGAATGAGTACTTTA 60 0.9 CBLB 868 Cblb 208650 ND000026ATCGAACATCCCAGATTTAGG 61 1.0 CBLB 868 Cblb 208650 ND000029TAAAGTGTACTGGTCCATTAG 62 1.4 CBLB 868 Cblb 208650 TRCN0000244607CTTGTACTCCAGTACCATAAT 63 1.5 CBLB 868 Cblb 208650 ND000028GTATGAGACAGAAGGACTGAG 64 1.5 CBLB 868 Cblb 208650 TRCN0000244604CCAGATTTAGGCATCTATTTG 65 1.6 CBLB 868 Cblb 208650 ND000031TCAGCACTTGAGACTTATATT 66 1.7 CBLB 868 Cblb 208650 ND000024TACACCTCACGATCATATAAA 67 2.1 CBLB 868 Cblb 208650 ND000033AACACAGACGCCATGATTTGC 68 5.1 CBLB 868 Cblb 208650 ND000032AAGATGTCAAGATTGAGCCTT 69 5.3 CBLB 868 Cblb 208650 TRCN0000244606CCCTGATTTAACCGGATTATG 70 6.1 CBLB 868 Cblb 208650 ND000030AGCCAGGTCCAATTCCATTTC 71 10.0 CBLB 868 Cblb 208650 ND000025CGAGCGATCCGGCTCTTTAAA 72 10.8 CBLB 868 Cdkn2a 12578 ND000317CTTGGTGAAGTTCGTGCGATC 73 0.6 CDKN2A 1029 Cdkn2a 12578 TRCN0000257162CGCTCTGGCTTTCGTGAACAT 74 0.8 CDKN2A 1029 Cdkn2a 12578 TRCN0000362594GATGATGATGGGCAACGTTCA 75 0.9 CDKN2A 1029 Cdkn2a 12578 TRCN0000231228TCCCAAGAGCAGAGCTAAATC 76 0.9 CDKN2A 1029 Cdkn2a 12578 TRCN0000362666TCTTGGTGAAGTTCGTGCGAT 77 1.0 CDKN2A 1029 Cdkn2a 12578 TRCN0000362596ACGGGCATAGCTTCAGCTCAA 78 1.1 CDKN2A 1029 Cdkn2a 12578 TRCN0000222730GCTCGGCTGGATGTGCGCGAT 79 1.1 CDKN2A 1029 Cdkn2a 12578 TRCN0000231225TTGAGGCTAGAGAGGATCTTG 80 1.2 CDKN2A 1029 Cdkn2a 12578 TRCN0000222731CATCAAGACATCGTGCGATAT 81 2.1 CDKN2A 1029 Cdkn2a 12578 TRCN0000077815GTGAACATGTTGTTGAGGCTA 82 2.3 CDKN2A 1029 Cdkn2a 12578 TRCN0000077816GTCTTTGTGTACCGCTGGGAA 83 3.3 CDKN2A 1029 Cdkn2a 12578 TRCN0000362595CTAGCGATGCTAGCGTGTCTA 84 4.1 CDKN2A 1029 Cdkn2a 12578 TRCN0000222729GTGATGATGATGGGCAACGTT 85 5.6 CDKN2A 1029 Cdkn2a 12578 TRCN0000231226GCTCAACTACGGTGCAGATTC 86 6.9 CDKN2A 1029 Cdkn2a 12578 TRCN0000231227TCAAGACATCGTGCGATATTT 87 7.2 CDKN2A 1029 Dgka 13139 TRCN0000024825GAGCTAAGTAAGGTGGTATAT 88 0.7 DGKA 1606 Dgka 13139 TRCN0000368765GCGATGTACTGAAGGTCTTTG 89 0.7 DGKA 1606 Dgka 13139 ND000059TCAGTGATGTGTACTGCTACT 90 0.8 DGKA 1606 Dgka 13139 ND000054GTATATCTCGACCGATGGTTC 91 1.0 DGKA 1606 Dgka 13139 TRCN0000378505TGATGCGAGTGGCCGAATATC 92 1.1 DGKA 1606 Dgka 13139 TRCN0000024828CCTAGGATTTGAACAATTCAT 93 1.2 DGKA 1606 Dgka 13139 ND000058AAAGATTCTCAAGGATATAGA 94 1.6 DGKA 1606 Dgka 13139 ND000056GAGGGATGTTCCATCACCTTC 95 1.9 DGKA 1606 Dgka 13139 ND000053TACAGACATCCTTACACAACC 96 2.0 DGKA 1606 Dgka 13139 TRCN0000024824GCCGAATATCTAGACTGGGAT 97 3.4 DGKA 1606 Dgka 13139 TRCN0000024827CGGCTGGAAGTGGTAGGAATA 98 3.5 DGKA 1606 Dgka 13139 ND000055GTTCCTCAGTTCCGGATATTG 99 5.0 DGKA 1606 Dgka 13139 TRCN0000024826CCTGAGCTGTAACTTCTGTAA 100 6.8 DGKA 1606 Dgka 13139 ND000057TGCGAACAGAGCATTAGCCTT 101 7.8 DGKA 1606 Dgka 13139 TRCN0000361167TGTTCCTCAGTTCCGGATATT 102 10.2 DGKA 1606 Dgkz 104418 ND000063CACCTTCCACAGCAAGGAGAT 103 0.4 DGKZ 8525 Dgkz 104418 ND000061ATCGTGGTGCATACCCAATGC 104 0.4 DGKZ 8525 Dgkz 104418 TRCN0000278613CCTGGATGTCTTTAACAACTA 105 0.7 DGKZ 8525 Dgkz 104418 ND000060CGAGTAGTGTGTGACGGAATG 106 0.9 DGKZ 8525 Dgkz 104418 ND000065CACATCTGGTTTGAGACCAAC 107 1.4 DGKZ 8525 Dgkz 104418 TRCN0000278690GAGAAGTTCAACAGCCGCTTT 108 1.6 DGKZ 8525 Dgkz 104418 ND000069ACTGTGCAGGCACCATGCCCT 109 2.0 DGKZ 8525 Dgkz 104418 ND000068AGAAGCTGTTCAGATCTAGGG 110 2.8 DGKZ 8525 Dgkz 104418 TRCN0000297512GTGGACTTCAAAGAATTCATT 111 3.6 DGKZ 8525 Dgkz 104418 ND000064ACTACGAGGCTCTACATTATG 112 5.2 DGKZ 8525 Dgkz 104418 ND000067AGTACATAATTTGAGGATTCT 113 5.5 DGKZ 8525 Dgkz 104418 TRCN0000278682CGAGGCTCTACATTATGACAA 114 6.0 DGKZ 8525 Dgkz 104418 TRCN0000278614CCTGTAAGATCGTGGTGCATA 115 6.4 DGKZ 8525 Dgkz 104418 ND000052GAAACCGCAGTGCATCGTCTT 116 7.7 DGKZ 8525 Dgkz 104418 ND000066CAGCATCACGGATTCGAATTG 117 14.0 DGKZ 8525 Egr2 13654 TRCN0000218224AGGATCCTTCAGCATTCTTAT 118 0.4 EGR2 1959 Egr2 13654 ND000075AGCTCTGGCTGACACACCAG 119 0.6 EGR2 1959 Egr2 13654 TRCN0000081682CCAGGATCCTTCAGCATTCTT 120 0.6 EGR2 1959 Egr2 13654 TRCN0000081678GCTGTATATTTCTGCCTATTA 121 1.3 EGR2 1959 Egr2 13654 TRCN0000235777ACTATTGTGGCCGCAAGTTTG 122 1.3 EGR2 1959 Egr2 13654 TRCN0000235775AGCGGGTACTACCGTTTATTT 123 1.6 EGR2 1959 Egr2 13654 TRCN0000235778CTGTATATTTCTGCCTATTAA 124 2.4 EGR2 1959 Egr2 13654 ND000073GTGACCACCTTACTACTCACA 125 3.2 EGR2 1959 Egr2 13654 ND000074GTTTGCCAGGAGTGACGAAAG 126 3.9 EGR2 1959 Egr2 13654 TRCN0000081681CCTTCACCTACATGGGCAAAT 127 4.0 EGR2 1959 Egr2 13654 TRCN0000081680CCAGAAGGTATCATCAATATT 128 5.1 EGR2 1959 Egr2 13654 TRCN0000081679CCACTCTCTACCATCCGTAAT 129 5.2 EGR2 1959 Egr2 13654 ND000072CCGTGCCAGAGAGATCCACAC 130 5.6 EGR2 1959 Egr2 13654 ND000071CAATAGGTTGGGAGTTGCTGA 131 8.6 EGR2 1959 Egr2 13654 TRCN0000235776ACTCTCTACCATCCGTAATTT 132 10.2 EGR2 1959 Eif2ak3 13666 TRCN0000321872CCATGAGTTCATCTGGAACAA 133 0.4 EIF2AK3 9451 Eif2ak3 13666 ND000328CATAGCTCCTTCTCCTGAAAG 134 0.9 EIF2AK3 9451 Eif2ak3 13666 ND000332GATGACTGCAATTACGCTATC 135 1.1 EIF2AK3 9451 Eif2ak3 13666 ND000325GTCGCCATTTATGTCGGTAGT 136 1.1 EIF2AK3 9451 Eif2ak3 13666 ND000325TGGAAACAACTACTCCCATAA 137 1.1 EIF2AK3 9451 Eif2ak3 13666 TRCN0000321873GTGACCCATCTGCACTAATTT 138 1.3 EIF2AK3 9451 Eif2ak3 13666 ND000329GCATGATGGCAACCATTATGT 139 1.3 EIF2AK3 9451 Eif2ak3 13666 ND000330ATCCCGATATCTAACAGATTT 140 1.6 EIF2AK3 9451 Eif2ak3 13666 ND000333TGTCGCCGATGGGATAGTGAT 141 1.9 EIF2AK3 9451 Eif2ak3 13666 TRCN0000321805GCCACTTTGAACTTCGGTATA 142 2.0 EIF2AK3 9451 Eif2ak3 13666 TRCN0000028759CCATACGATAACGGTTACTAT 143 4.8 EIF2AK3 9451 Eif2ak3 13666 TRCN0000321806CCTCTACTGTTCACTCAGAAA 144 5.8 EIF2AK3 9451 Eif2ak3 13666 ND000327CATACGATAACGGTTACTATC 145 5.9 EIF2AK3 9451 Eif2ak3 13666 ND000331CGTGACCCATCTGCACTAATT 146 7.3 EIF2AK3 9451 Eif2ak3 13666 TRCN0000028799GCCTGTTTGATGATACAAGTT 147 13.4 EIF2AK3 9451 Entpd1 12495 ND000082GAATGTAAGTGAGCTCTATGG 148 0.3 ENTPD1 953 Entpd1 12495 TRCN0000222348CCGAACTGATACCAACATCCA 149 0.4 ENTPD1 953 Entpd1 12495 TRCN0000222346CCCATGCTTTAACCCAGGATA 150 0.4 ENTPD1 953 Entpd1 12495 TRCN0000222345COETGGTTTCACCTCTATCTT 151 0.8 ENTPD1 953 Entpd1 12495 TRCN0000222344CCAAGGACATTCAGGTTTCAA 152 0.9 ENTPD1 953 Entpd1 12495 ND000085CAGGAACAGAGTTGGCTAAGC 153 1.0 ENTPD1 953 Entpd1 12495 ND000078TTAACCCAGGATACGAGAAGG 154 1.1 ENTPD1 953 Entpd1 12495 ND000081ACTATCTCAGCCATGGCTTTG 155 1.2 ENTPD1 953 Entpd1 12495 ND000077TTCAAGTGGTGGCGTCCTTAA 156 1.3 ENTPD1 953 Entpd1 12495 ND000076GACTTTGGGCTACATGCTGAA 157 1.4 ENTPD1 953 Entpd1 12495 ND000080GGCATGCGCTTGCTTAGAATG 158 1.9 ENTPD1 953 Entpd1 12495 ND000084GCACTGGAGACTACGAACAGT 159 1.9 ENTPD1 953 Entpd1 12495 ND000083GTGGATTACTATTAACTATCT 160 6.5 ENTPD1 953 Entpd1 12495 TRCN0000222347GCTCCTGGGAACAGATTCATT 161 7.3 ENTPD1 953 Entpd1 12495 ND000079ACCATTTGATCAGTTTCGAAT 162 13.3 ENTPD1 953 F11r 16456 TRCN0000284518GCTGATTCCCAGGACTATATT 163 0.6 F11R 50848 F11r 16456 TRCN0000124868GTATCGCTGTATAACTATGTA 164 0.6 F11R 50848 Fllr 16456 ND000093ATTGACCTGCACCTACTCT 165 0.6 F11R 50848 Fllr 16456 ND000094GCCGGGAGGAAACTGTTGT 166 0.6 F11R 50848 Fllr 16456 TRCN0000271840CCTGGTTCAAGGACGGGATAT 167 0.7 F11R 50848 Fl1r 16456 TRCN0000271841TTCGGTGTACACTGCTCAATC 168 0.7 F11R 50848 Fl1r 16456 TRCN0000271792CACCGGGTAAGAAGGTCATTT 169 0.9 F11R 50848 Fl1r 16456 ND000088ACTTGCATGGTCTCCGAGGAA 170 0.9 F11R 50848 Fl1r 16456 ND000086GTAACACTGATTLTCCTTGGA 171 1.0 F11R 50848 Fllr 16456 ND000090GTTATAACAGCCAGATCACAG 172 1.1 F11R 50848 Fllr 16456 ND000092TAGCTGCACAGGATGCCTTCA 173 1.3 F11R 50848 Fllr 16456 ND000087GGTTTGCCTATAGCCGTGGAT 174 1.9 F11R 50848 Fllr 16456 TRCN0000271794CCTATAGCCGTGGATACTTTG 175 4.3 F11R 50848 Fllr 16456 ND000091CTCCGTTGTCCATTTGCCTTA 176 4.6 F11R 50848 F11r 16456 ND000089CCACCCTCTGAATATTCCTGG 177 6.8 F11R 50849 Fyn 14360 TRCN0000023383CATCCCGAACTACAACAACTT 178 0.7 FYN 2534 Fyn 14360 TRCN0000023381CCTTTGGAAACCCAAGAGGTA 179 0.9 FYN 2534 Fyn 14360 TRCN0000361148TCTGAGACAGAAGCGTGTTAT 180 1.4 FYN 2534 Fyn 14360 TRCN0000023379GCTCGGTTGATTGAAGACAAT 181 1.4 FYN 2534 Fyn 14360 TRCN0000361213TTGACAATGGTGGATACTATA 182 1.9 FYN 2534 Fyn 14360 TRCN0000361149TCTTCACCTGATTCAACTAAA 183 1.9 FYN 2534 Fyn 14360 TRCN0000023382GCTCTGAAGTTGCCAAACCTT 184 2.0 FYN 2534 Fyn 14360 TRCN0000361212CACTGTTTGTGGCGCTTTATG 185 2.3 FYN 2534 Fyn 14360 TRCN0000361152CATCGAGCGCATGAATTATAT 186 2.9 FYN 2534 Fyn 14360 TRCN0000023380CCTGTATGGAAGGTTCACAAT 187 6.5 FYN 2534 Fyn 14360 ND000111TCGATGTTATGTCAAAGGCC 188 0.5 FYN 2534 Fyn 14360 ND000112ACCACACAAACTTCCTGTAT 189 0.7 FYN 2534 Fyn 14360 ND000115ACAGCTCCTGTCCTTTGGAAA 190 1.0 FYN 2534 Fyn 14360 ND000113GCAGCGAAACTGACAGAGGAG 191 4.1 FYN 2534 Fyn 14350 ND000114ACACTGTTTGTGGCGCTTTAT 192 4.4 FYN 2534 Grk6 26385 ND000356TGACTACCACAGCCTATGTGA 193 0.5 GRK6 2870 Grk6 26385 TRCN0000022851CGAGAAACAGATCTTGGAGAA 194 0.6 GRK6 2870 Grk6 26385 ND000355CTAACCTTGCTTAGCAACTGT 195 0.6 GRK6 2870 Grk6 26385 ND000359AGGAATGAGCGCTACACGTTC 196 1.0 GRK6 2870 Grk6 26385 TRCN0000022853TCTTGGAGAAAGTGAACAGTA 197 1.1 GRK6 2870 Grk6 26385 TRCN0000022850GCGCCTGTTATTTCGTGAGTT 198 1.1 GRK6 2870 Grk6 26385 TRCN0000361581GAACAGTTCTCTACAGTTAAA 199 1.1 GRK6 2870 Grk6 26385 ND000354CAGGCTATTTATTGCAAGGAT 200 1.2 GRK6 2870 Grk6 26385 ND000357GAGCTTAGCCTACGCCTATGA 201 1.3 GRK6 2870 Grk6 26385 TRCN0000022852GCAAAGGCAAGAGCAAGAAAT 202 1.3 GRK6 2870 Grk6 26385 TRCN0000361580CCATGGCTCTCAACGAGAAAC 203 2.7 GRK6 2870 Grk6 26385 ND000358TCTATGCTGCTGAGATCTGCT 204 4.2 GRK6 2870 Grk6 26385 TRCN0000361508GCCGACTAATGCAGAACTTTC 205 4.5 GRK6 2870 Grk6 26385 ND000360CGCCTGTTATTTCGTGAGTTC 206 5.8 GRK6 2870 Grk6 26385 TRCN0000022849CGCCGACTAATGCAGAACTTT 207 11.0 GRK6 2870 Hipk1 15257 ND000371CTACCTGCAATCACGCTACTA 208 0.3 HIPK1 204851 Hipk1 15257 ND000374AGCGGAGGGTTCACATGTATG 209 0.4 HIPK1 204851 Hipk1 15257 TRCN0000361231CAACCAGTACAGCACTATTAT 210 0.4 HIPK1 204851 Hipk1 15257 TRCN0000361237TACCCTTTTTCTGGCTAATTC 211 0.7 HIPK1 204851 Hipk1 15257 TRCN0000368011AGCCTGAAGGCGAGGTCTAAT 212 1.1 HIPK1 204851 Hipk1 15257 ND000375CATTGGCACCCGTACTATCAT 213 1.1 HIPK1 204851 Hipk1 15257 TRC80000023157GCTTCAGAATACGATCAGATT 214 1.2 HIPK1 204851 Hipk1 15257 ND000375GAAGACTCTTAACCACCAATT 215 1.8 HIPK1 204851 Hipk1 15257 TRCN0000361233ATACGATCAGATTCGCTATAT 216 1.9 HIPK1 204851 Hipk1 15257 ND000372CTGTCATACATTTGGTCTCTT 217 2.7 HIPK1 204851 Hipk1 15257 ND000377GCTACTAGCCCTGAGTTCTTA 218 3.4 HIPK1 204851 Hipk1 15257 TRCN0000361232TATAACTTTGTCCGTTCTTAT 219 4.5 HIPK1 204851 Hipk1 15257 ND000373CTCGCTGCTAAACTACCAATC 220 6.3 HIPK1 204851 Hipk1 15257 ND000378GCCAATCATCATTCCAGATAC 221 6.7 HIPK1 204851 Hipk1 15257 TRCN0000023154CGCTCCAAATACAAGCACAAA 222 12.3 HIPK1 204851 Inpp5b 16330 TRCN0000080903GCTTAGAGGTTCCTGGATAAA 223 0.5 INPP5B 3633 Inpp5b 16330 TRCN0000080906CCTTTGGTTCACACACCAGAA 224 0.7 INPP5B 3633 Inpp5b 16330 ND000130CTGTTAGTGACCTGACGTTGA 225 0.8 INPP5B 3633 Inpp5b 16330 TRCN0000305895ATATTCTAGCTAGCATATTTG 226 0.8 INPP5B 3633 Inpp5b 16330 TRCN0000311434GGCCAGAGTTTGACCATATAA 227 1.4 INPP5B 3633 Inpp5b 16330 ND000131GAGTCCTTCACGATTCATAAT 228 1.4 INPP5B 3633 Inpp5b 16330 TRCN0000080905CGGATCTCCTATCCATACATT 229 1.5 INPP5B 3633 Inpp5b 16330 ND000128GTATCGGACAAGGCTCACATT 230 1.6 INPP5B 3633 Inpp5b 16330 ND000129TTCGAGACACAATCGTGAGAT 231 1.9 INPP5B 3633 Inpp5b 16330 ND000127CTGTCCAAGCCGCAAACATGT 232 3.1 INPP5B 3633 Inpp5b 16330 ND000133CTCAAGCTTGTATTCCAACTT 233 4.3 INPP5B 3633 Inpp5b 16330 ND000132ATATAAGGGACTGTCTAGATA 234 4.6 INPP5B 3633 Inpp5b 16330 TRCN0000080904CGAGTCCTTCACGATTCATAA 235 6.2 INPP5B 3633 Inpp5b 15330 TRCN0000080907CCGAGTCCTTCACGATTCATA 236 8.1 INPP5B 3533 Inpp5b 16330 ND000134CGTCCGACTGGTTGGGATTAT 237 9.5 INPP5B 3633 Ipmk 69718 TRCN0000024840CCCAGATGGTACAGTTCTGAA 238 0.5 IPMK 253430 Ipmk 69718 ND000384CGAGGCTGTGTGGGTTCTATA 239 0.5 IPMK 253430 Ipmk 69718 TRCN0000360733TTGCCGTGCTTCGGAGTATTT 240 0.6 IPMK 253430 Ipmk 69718 TRCN0000360808GATGCGATTGCCGCCAGTATT 241 0.7 IPMK 253430 Ipmk 69718 TRCN0000024839CCTAACGAAAGAGACCCTGAA 242 0.8 IPMK 253430 Ipmk 69718 ND000383ATTGCCGTGCTTCGGAGTATT 243 1.1 IPMK 253430 Ipmk 69718 ND000380AGCGGAAGTACGGATGATAGA 244 1.3 IPMK 253430 Ipmk 69718 TRCN0000360807GAGGCTCTGTGGGTTCTATAT 245 1.4 IPMK 253430 Ipmk 69718 ND000379TGCCCAAATACTACGGCGTCT 246 1.7 IPMK 253430 Ipmk 69718 TRCN0000024843CGGCAAGGACAAAGTGGGCAT 247 2.9 IPMK 253430 Ipmk 69718 ND000381CTAGCAACACAGTCGATGAGG 248 3.2 IPMK 253430 Ipmk 69718 TRCN0000360732ACCAAACGATGTGTACCTAAA 249 4.0 IPMK 253430 Ipmk 69718 TRCN0000024841ACCCTGTATAATGGACGTGAA 250 4.1 IPMK 253430 Ipmk 69718 ND000382CCTGTATAATGGACGTGAAGA 251 4.7 IPMK 253430 Ipmk 69718 TRCN0000024842CACCAAACGATGTGTACCTAA 252 6.9 IPMK 253430 Jun 16476 TRCN0000229526GAACAGGTGGCACAGCTTAAG 253 0.5 JUN 3725 Jun 16476 TRCN0000042693CGGCTACAGTAACCCTAAGAT 254 0.5 JUN 3725 Jun 16476 TRCN0000055205CTACGCCAACCTCAGCAACTT 255 0.7 JUN 3725 Jun 16476 TRCN0000055206CGGTGCCTACGGCTACAGTAA 256 0.8 JUN 3725 Jun 16476 TRCN0000042695GCTTAAGCAGAAAGTCATGAA 257 0.9 JUN 3725 Jun 16476 TRCN0000360499AGCGCATGAGGAACCGCATTG 258 0.9 JUN 3725 Jun 16476 TRCN0000360498CCTATCGACATGGAGTCTCAG 259 0.9 JUN 3725 Jun 16476 TRCN0000042697GAAGCGCATGAGGAACCGCAT 260 1.0 JUN 3725 Jun 16476 TRCN0000360511ATTCGATCTCATTCAGTATTA 261 1.1 JUN 3725 Jun 16476 TRCN0000360572GGATCGCTCGGCTAGAGGAAA 262 1.2 JUN 3725 Jun 16476 TRCN0000055207GCGGATCAAGGCAGAGAGGAA 263 3.1 JUN 3725 Jun 16476 TRCN0000229528GGCATGTGCTGTGATCATTTA 264 3.2 JUN 3725 Jun 16476 TRCN0000042694ACGCAGCAGTTGCAAACGTTT 265 3.3 JUN 3725 Jun 16476 TRCN0000055203GCGGGGTAACTGCAATAAGAT 266 5.2 JUN 3725 Jun 16476 TRCN0000229525CAGTAACCCTAAGATCCTAAA 267 5.5 JUN 3725 Jun 16476 TRCN0000229527GCTAACGCAGCAGTTGCAAAC 268 5.8 JUN 3725 Jun 16476 TRCN0000218856GAAAGTCATGAACCACGTTAA 269 6.4 JUN 3725 Mast2 17776 TRCN0000225743AGCAACAACAGGAAGGTATAT 270 0.4 MAST2 23139 Mast2 17776 TRCN0000022896GCATCCACGAACAAGACCATA 271 0.7 MAST2 23139 Mast2 17776 TRCN0000225741TTGAGACCAAGCGTCACTTAT 272 1.0 MAST2 23139 Mast2 17776 ND000396CCGCAAGAGCTTGATTGTAAC 273 1.2 MAST2 23139 Mast2 17776 TRCN0000022898GCTGGTTCTGAAGAGTGGAAA 274 1.2 MAST2 23139 Mast2 17776 ND000392GATATTACGGAAGCGGTTATC 275 1.3 MAST2 23139 Mast2 17776 ND000393ACGAATACCACGGTCCCAAAT 276 1.4 MAST2 23139 Mast2 17776 ND0218393GTGGAAACAAGGTATCAATTT 277 1.5 MAST2 23139 Mast2 17776 ND000397GAAGTGTGCTATCCGGGAAAG 278 1.6 MAST2 23139 Mast2 17776 ND000395GCCTCATTACGTCACACTATT 279 1.6 MAST2 23139 Mast2 17776 TRCN0000022895CCTCATTACGTCACACTATTT 280 1.9 MAST2 23139 Mast2 17776 TRCN0000225742ACTTGTATGAGGGTCATATTG 281 4.1 MAST2 23139 Mast2 17776 TRCN0000022897CGAATGAGAAACCAATCCCTT 282 4.2 MAST2 23139 Mast2 17776 ND000394GCATCAAACCTGGTTCGAATG 283 4.3 MAST2 23139 Mast2 17776 TRCN0000022894CCCTGTCAACAAAGTAATCAA 284 5.1 MAST2 23139 Mdfic 16543 TRCN0000237997GGAGGAAACAGGCAAGATAAA 285 0.2 MDFIC 29969 Mdfic 16543 TRCN0000237994TGATGCGGGACCAGTCCATTT 286 0.4 MDFIC 29969 Mdfic 16543 ND000148TGTAATGAGGACAATACGGAG 287 0.4 MDFIC 29969 Mdfic 16543 TRCN0000362432TCCTGACCCTCTGCAACATTG 288 0.6 MDFIC 29969 Mdfic 16543 TRCN0000237996TGACATGGACTGCGGCATCAT 289 0.8 MDFIC 29969 Mdfic 16543 TRCN0000095981CGAAGCATGTAATGAGGACAA 290 1.0 MDFIC 29969 Mdfic 16543 TRCN0000095982GACATCAGTAAGAAGAGTAAA 291 1.1 MDFIC 29969 Mdfic 16543 TRCN0000237998TGCCAAGTGACAGGTTATAAA 292 1.1 MDFIC 29969 Mdfic 16543 TRCN0000095983TGCAACATTGTCCTGGGACAA 293 1.5 MDFIC 29969 Mdfic 16543 TRCN0000237995ATCGTCAGACTGTCTAGAAAT 294 1.6 MDFIC 29969 Mdfic 16543 TRCN0000095980CCGTGGAGAATCACAAGATAT 295 2.6 MDFIC 29969 Mdfic 16543 TRCN0000362509GTTTATCTATTGGAGGTTAAA 296 4.4 MDFIC 29969 Mdfic 16543 ND000147GAAGAGTAAAGTAAATGCTGT 297 5.1 MDFIC 29969 Mdfic 16543 TRCN0000095979CGCCGGATGTATGTGGTTTAA 298 7.2 MDFIC 29969 Mdfic 16543 TRCN0000362431GCCGGATGTATGTGGTTTAAT 299 10.0 MDFIC 29969 Nptxr 73340 TRCN0000219475CTTGGTCTCTCCCATCATATA 300 0.5 NPTXR 23467 Nptxr 73340 ND000150ACAGCAACTGGCACCATATCT 301 0.8 NPTXR 23467 Nptxr 73340 TRCN0000219474GATACCTTGGGAGGCCGATTT 302 0.8 NPTXR 23467 Nptxr 73340 ND000155GGCCAATGAGATCGTGCTTCT 303 1.0 NPTXR 23467 Nptxr 73340 ND000154GTAGCCTTTGACCCTCAAATC 304 1.0 NPTXR 23467 Nptxr 73340 ND000152CAATGGAGCTGCTGATCAACG 305 1.0 NPTXR 23467 Nptxr 73340 TRCN0000219472GACAGCAACTGGCACCATATC 306 1.1 NPTXR 23467 Nptxr 73340 ND000158TTGGTCTCTCCCATCATATAC 307 1.3 NPTXR 23467 Nptxr 73340 ND000159ATACCTTGGGAGGCCGATTTG 308 1.3 NPTXR 23467 Nptxr 73340 ND000133CCTGTCAGTTTCAGGACTTTG 309 2.0 NPTXR 23467 Nptxr 73340 ND000156TCCGCAACAACTACATGTACG 310 2.1 NPTXR 23467 Nptxr 73340 ND000157ATAAGCTGGTAGAGGCCTTTG 311 3.9 NPTXR 23467 Nptxr 73340 ND000149CGGTGCCGTCATCTGCATCAT 312 6.6 NPTXR 23467 Nptxr 73340 TRCN0000219473CAAGCCACACGGCATCCTTAT 313 7.0 NPTXR 23467 Nptxr 73340 ND000151TCAAGCCACACGGCATCCTTA 314 7.2 NPTXR 23467 Nuak2 74137 ND000434TTGGACTTGCCTGAACGTCTT 315 0.2 NUAK2 81788 Nuak2 74137 TRCN0000361812TTTGACGGGCAGGATCATAAA 316 0.4 NUAK2 81788 Nuak2 74137 TRCN0000024271GCCAATGGAAACATCAAGATT 317 0.7 NUAK2 81788 Nuak2 74137 TRCN0000361873GTGTAGTGACTGCCATTATTT 318 0.7 NUAK2 81788 Nuak2 74137 ND000436CCAAGGTGTGCAGCTTCTTCA 319 1.6 NUAK2 81788 Nuak2 74137 ND000431CCTGATCCGGTGGCTGTTAAT 320 1.7 NUAK2 81788 Nuak2 74137 TRCN0000378457GGGCTCATCAAGTCGCCTAAA 321 1.8 NUAK2 81788 Nu3k2 74137 TRCN0000024270CCGAAAGGCATTCTCAAGAAA 322 2.1 NUAK2 81788 Nu3k2 74137 TRCN0000024273GTCGCCTAAACCTCTGATGAA 323 2.1 NUAK2 81788 Nuak2 74137 TRCN0000024272CCGAGGCGATCTGTATGATTA 324 2.1 NUAK2 81788 Nuak2 74137 TRCN0000378409GAAGTCTCGACAGCGTGAATC 325 2.8 NUAK2 81788 Nuak2 74137 ND000435TCGGACCGCTGTTTGACTTCA 326 2.8 NUAK2 81788 Nuak2 74137 ND000433TAGCAGCAAGATTGTGATTGT 327 4.5 NUAK2 81788 Nuak2 74137 ND000432AGTCTCGACAGCGTGAATCTG 328 5.4 NUAK2 81788 Nuak2 74137 TRCN0000024269CCCAAGGAAAGGCATCCTTAA 329 13.1 NUAK2 81788 Pdzk1ip1 67182 TRCN0000244507GATGGCAGATACTCCTCAATG 330 0.4 PDZK1IP1 10158 Pdzk1ip1 67182 ND000172GGGAATGGATGGCAGATACTC 331 0.5 PDZK1IP1 10158 Pdzk1ip1 67182 ND000176CTCCCTCACCTCTCTAGAATC 332 0.6 PDZK1IP1 10158 Pdzk1ip1 67182 ND000170TGCAATCGTCTTCGCCGTCAA 333 0.8 PDZK1IP1 10158 Pdzk1ip1 67182 ND000173CATTGCTGTCGCTGTGTTCTT 334 1.2 PDZK1IP1 10158 Pdzk1ip1 67182TRCN0000244505 ACAAGAATGCCTACGAGAATG 335 1.7 PDZK1IP1 10158 Pdzk1ip167182 ND000174. TTCTTGGTCCTTGTTGCAATC 336 2.0 PDZK1IP1 10158 Pdzk1ip167182 TR0ND000244509 GGAGCACAGTGATGATCATTG 337 2.5 PDZK1IP1 10158Pdzk1ip1 67182 ND000171 ACTGCTCTACAGGAATCTACT 338 2.5 PDZK1IP1 10158Pdzk1ip1 67182 ND000175 CTGTCAACAAGGTCTAGGAAA 339 4.8 PDZK1IP1 10158Pdzk1ip1 67182 TRCN0000244508 CCTCATTGCTGTCGCTGTGTT 340 6.3 PDZK1IP110158 Pdzk1ip1 67182 TRCN0000244506 TCTACAGGAATCTACTGAAAC 341 12.9PDZK1IP1 10158 Pkd1 18763 ND000445 CAAGTCCTATGACCCTAATTT 342 0.5 PKD15310 Pkd1 18763 TRCN0000304664 GGTGGACACCACTCAGTATTA 343 0.8 PKD1 5310Pkd1 18763 TRCN0000072086 CCAACTCAACATCACCGTAAA 344 0.8 PKD1 5310 Pkd118763 TRCN0000304612 ACACAATACCACGCATATTTA 345 0.9 PKD1 5310 Pkd1 18763ND000447 GGCCGCTTCAAATATGAAATA 346 1.2 PKD1 5310 Pkd1 18763 ND000444TTCACTAGGAGTGGCATATTC 347 1.3 PKD1 5310 Pkdl 18763 ND000442CATCTATAAGGGTAGTCTTTC 348 1.4 PKD1 5310 Pkd1 18763 ND000441GTTATTACCTCTCTTGTTTCT 349 1.8 PKD1 5310 Pkd1 18763 ND000446GTAGTCTACCCTGTCTATTTG 350 2.9 PKD1 5310 Pkd1 18763 TRCN0000072084GCCCTGTACCTTTCAACCAAT 351 4.9 PKD1 5310 Pkd1 18763 ND000443CATGTCATCGAGTACTCTTTA 352 6.2 PKD1 5310 Pkd1 18763 TRCN0000304611CAACTGATGGTGTCCTATATA 353 7.7 PKD1 5310 Pkd1 18763 TRCN0000072085CCATCATTGAAGGTGGCTCAT 354 8.9 PKD1 5310 Pkd1 18763 TRCN0000072087GCTTCACTACTCTTCCTGCTT 355 9.9 PKD1 5310 Pkd1 18763 TRCN0000331808CGCTCGCACTTTCAGCAATAA 356 47.6 PKD1 5310 Ppm1g 14208 TRCN0000326875GAGGATGATAAAGACAAAGTA 357 0.3 PPM1G 5496 Ppm1g 14208 TRCN0000326874GCTTTCCTCAGCCCATTACAA 358 0.5 PPM1G 5496 Ppm1g 14208 ND000458GAGATGATGGTCCCTGGAATG 359 0.8 PPM1G 5496 Ppm1g 14208 TRCN0000375841TGACCACAGAGGAAGTCATTA 360 1.1 PPM1G 5496 Ppm1g 14208 TRCN0000081212GATGCCTTCTTGGCTATTGAT 361 1.1 PPM1G 5496 Ppm1g 14208 TRCN0000306418CCATGGATGGACGAGTCAATG 362 1.2 PPM1G 5496 Ppm1g 14208 ND000460TGACGCGATATGGGCAGAACT 363 1.2 PPM1G 5496 Ppm1g 14208 ND000464GCTACCATGACTATTGAAGAG 364 1.3 PPM1G 5496 Ppm1g 14208 ND000462TGGCAAAGCTTTAGATATGTC 365 2.1 PPM1G 5496 Ppm1g 14208 ND000465CATGGATGGACGAGTCAATGG 366 2.9 PPM1G 5496 Ppm1g 14208 TRCN0000081210CTTCGGTTATTGTCATCCATT 367 3.0 PPM1G 5496 Ppm1g 14208 ND000459TGCCTGTGCTCTGTTGTGTTG 368 3.6 PPM1G 5496 Ppm1g 14208 ND000461CAAATTAGTGAGCCCGGTACT 369 6.2 PPM1G 5496 Ppm1g 14208 TRCN0000081209GCCTTGTACTGTGCCAAATAT 370 7.1 PPM1G 5496 Ppm1g 14208 ND000463CATGACGTGCATCATCATTTG 371 8.5 PPM1G 5496 Ppp2r2d 52432 ND000490ACTTCGAGACCCATTTAGAAT 372 0.7 PPP2R2D 55844 Ppp2r2d 52432 ND000488CAGAAGATCCCAGCAGTAGAT 373 0.9 PPP2R2D 55844 Ppp2r2d 52432 TRCN0000030899GCCACCAATAACTTGTATATA 374 1.0 PPP2R2D 55844 Ppp2r2d 52432 TRCN0000430828ATAGTGATCATGAAACATATC 375 1.3 PPP2R2D 55844 Ppp2r2d 52432 ND000487ATATGTACGCCGGTCAATTAG 376 1.4 PPP2R2D 55844 Ppp2r2d 52432 TRCN0000425449ATGCTCATACATATCACATAA 377 1.5 PPP2R2D 55844 Ppp2r2d 52432 TRCN0000427220TCATCTCCACCGTTGAGTTTA 378 1.6 PPP2R2D 55844 Ppp2r2d 52432 ND000491GATCTGAGAATTAACCTATGG 379 1.7 PPP2R2D 55844 Ppp2r2d 52432 TRCN0000080901CCATTTAGAATTACGGCACTA 380 1.9 PPP2R2D 55844 Ppp2r2d 52432 TRCN0000080902CGGTTCAGACAGTGCCATTAT 381 2.0 PPP2R2D 55844 Ppp2r2d 52432 ND000489CACCGTTGAGTTTAACTACTC 332 4.0 PPP2R2D 55844 Ppp2r2d 52432 ND000486GCTCAATAAAGGCCATTACTC 383 4.9 PPP2R2D 55844 Ppp2r2d 52432 TRCN0000431278GAGAATTAACCTATGGCATTT 384 8.3 PPP2R2D 55844 Ppp2r2d 52432 ND000492CCACAGTGGTCGATACATGAT 385 16.3 PPP2R2D 55844 Ppp2r2d 52432TRCN0000080900 CCCACATCAGTGCAATGTATT 386 17.2 PPP2R2D 55844 Ppp3cc 19057ND000512 CCCGAGGTCTAGACCGAATTA 387 0.1 PPP3CC 5533 Ppp3cc 19057 ND000510TCACAGTGTGTGGTGATGTTC 388 0.4 PPP3CC 5533 Ppp3cc 19057 TRCN0000012695GCTGTATCTATGGAGCTTAAA 389 0.4 PPP3CC 5533 Ppp3cc 19057 TRCN0000012693CCTATGAGCAAATCACATTTA 390 0.4 PPP3CC 5533 Ppp3cc 19057 ND000511AGGAATGTCGGATCAAGTATT 391 0.7 PPP3CC 5533 Ppp3cc 19057 TRCN0000012694CGGCTAACTTTGAAGGAAGTT 392 0.9 PPP3CC 5533 Ppp3cc 19057 TRCN0000012696CGGATGAAGAAATGAACGTAA 393 1.2 PPP3CC 5533 Ppp3cc 19057 ND000508ACCTAGTAATACTCGCTACCT 394 1.4 PPP3CC 5533 Ppp3cc 19057 ND000513CTGTATCTATGGAGCTTAAAG 395 1.6 PPP3CC 5533 Ppp3cc 19057 ND000515AGAAATGAACGTAACCGATGA 396 1.8 PPP3CC 5533 Ppp3cc 19057 ND000514CAAACAACTTAAACTTGGAGG 397 2.4 PPP3CC 5533 Ppp3cc 19057 ND000507TGTAATTCAGTCGCATTTATT 398 2.6 PPP3CC 5533 Ppp3cc 19057 ND000506GGACAATTCTTTGACCTGATG 399 4.2 PPP3CC 5533 Ppp3cc 19057 TRCN0000012697CGAGGTCTAGACCGAATTAAT 400 4.3 PPP3CC 5533 Ppp3cc 19057 ND000509TTCCGTCACTTATTACGATTT 401 4.4 PPP3CC 5533 Prkab2 108097 ND000529CTGTGGTTACCAGTCAGCTTG 402 0.2 PRKAB2 5565 Prkab2 108097 TRCN0000025112GTATGTCACCACGCTGCTGTA 403 0.4 PRKAB2 5565 Prkab2 108097 ND000527CCCTCACCTACTCCAAGTTAT 404 0.7 PRKAB2 5565 Prkab2 108097 TRCN0000361908TATGAGTTCACGGAGTTTATT 405 0.7 PRKAB2 5565 Prkab2 108097  TRCN0000025111CGCAACCCATCGCTACAAGAA 406 0.8 PRKAB2 5565 Prkab2 108097 TRCN0000025109CATCGCTACAAGAAGAAGTAT 407 0.9 PRKAB2 5565 Prkab2 108097 ND000528CAATTGGAGCACCAAGATCCC 408 1.1 PRKAB2 5565 Prkab2 103097 ND000530AGTGGGTTCATGATCCGTCAG 409 1.1 PRKAB2 5565 Prkab2 108097 ND000526ACCGTTATCCGCTGGTCTGAA 410 1.8 PRKAB2 5565 Prkab2 108097 TRCN0000361952GATCTGAGGAGAGATTCAAAT 411 2.0 PRKAB2 5565 Prkab2 108097 TRCN0000361953CTTAACAAGGACACGAATATT 412 2.3 PRKAB2 5565 Prkab2 108097 TRCN0000361910CTCTGATAAAGAGTCATAATG 413 2.6 PRKAB2 5565 Prkab2 108097 TRCN0000025110CGCTGCTGTATAAGCCCATCT 414 4.1 PRKAB2 5565 Prkab2 108097 ND000525CTTACGGTCAAGAAATGTATG 415 4.8 PRKAB2 5565 Prkab2 108097 TRCN0000025113CATTAAGGACAGTGTGATGGT 416 7.0 PRKAB2 5565 Ptpn2 19255 ND000532TCCGAACACATGCTGCCATTT 417 0.5 PTPN2 5771 Ptpn2 19255 TRCN0000029891GCCAAGATTGACAGACACCTA 418 1.0 PTPN2 5771 Ptpn2 19255 TRCN0000279253AGACTATTCTGCAGCTATAAA 419 1.0 PTPN2 5771 Ptpn2 19255 TRCN0000029893CCGTTATACTTGGAAATTCGA 420 1.0 PTPN2 5771 Ptpn2 19255 TRCN0000279254AGTATCGAATGGGACTTATTC 421 1.2 PTPN2 5771 Ptpn2 19255 ND000534TTATATTAATGCCAGCTTAGT 422 1.4 PTPN2 5771 Ptpn2 19255 ND000531ATGTTCATGACTTGAGACTAT 423 1.7 PTPN2 5771 Ptpn2 19255 TRCN0000279329ATATGATCACAGTCGTGTTAA 424 2.2 PTPN2 5771 Ptpn2 19255 TRCN0000279252CGGTGGAAAGAACTTTCTAAA 425 2.2 PTPN2 5771 Ptpn2 19255 ND000533CCATATCTCACTTCCATTATA 426 4.7 PTPN2 5771 Ptpn2 19255 TRCN0000279330TCTCCTACATGGCCATAATAG 427 5.0 PTPN2 5771 Ptpn2 19255 TRCN0000029890CGGTGGAAAGAACTTTCTAAA 428 5.1 PTPN2 5771 Ptpn2 19255 ND000535TATCGAATGGGACTTATTCAG 429 5.5 PTPN2 5771 Ptpn2 19255 TRCN0000029892CCTGTCTTGTTCTGATGGAAA 430 7.4 PTPN2 5771 Rbks 71336 ND000536TCGCTGCAGTCAGTGTACAGG 431 0.4 RBKS 611132 Rbks 71336 ND000543GGCCTTCTACCTGGCTTACTA 432 0.6 RBKS 611132 Rbks 71336 ND000537CTGCAATGATTCTCCTAGAAC 433 0.9 RBKS 611132 Rbks 71336 ND000544AGTGGTGGGTTCCTGCATGAC 434 0.9 RBKS 611132 Rbks 71336 ND000539ATATGCCAGCTAGAAATAAGC 435 1.1 RBKS 611132 Rbks 71336 TRCN0000078936GTGATGATATGCCAGCTAGAA 436 1.2 RBKS 611132 Rbks 71336 ND000538CATATTTCTACAGAGTTTACA 437 1.7 RBKS 611132 Rbks 71336 TRCN0000078934TCAATAATGAAGGCCAGAATA 438 1.9 RBKS 611132 Rbks 71336 ND000545GCTGCCAGGTTGTGGTCATCA 439 2.7 RBKS 611132 Rbks 71336 TRCN0000078937TGATGATATGCCAGCTAGAAA 440 4.0 RBKS 611132 Rbks 71336 ND000541CAAGGTTGGCAACGATTCTTT 441 4.1 RBKS 611132 Rbks 71336 ND000542GAGCCTGTTCCAAAGCACATT 442 5.0 RBKS 611132 Rbks 71336 TRCN000078935CCAAAGCACATTCCCACTGAA 443 5.7 RBKS 611132 Rbks 71336 ND000540CATTAGCCGAGCCAAAGTGAT 444 12.8 RBKS 611132 Rbks 71336 TRCN0000078933GCCTCCATAATTGTCAATAAT 445 13.9 RBKS 611132 Rock1 19877 ND000568CATACTGTTAGTCGGCTTGAA 446 0.6 ROCK1 6093 Rock1 19877 ND000567ATGACATGCAAGCGCAATTGG 447 0.7 ROCK1 6093 Rock1 19877 ND000555GCCTACAGGTAGATTAGATTA 448 0.9 ROCK1 6093 Rock1 19877 ND000569AGTTCAATTGGTGAGGCATAA 449 1.0 ROCK1 6093 Rock1 19877 TRCN0000361452CTAGCAAAGAGAGTGATATTG 450 1.2 ROCK1 6093 Rock1 19877 TRCN0000022901CCTGGTTTATGATTTGGATTT 451 1.6 ROCK1 6093 Rock1 19877 TRCN0000022900CGGGAGTTACAAGATCAACTT 452 1.7 ROCK1 6093 Rock1 19877 TRCN0000022902CCGTGCAAAGTAAGTTACGAT 453 1.8 ROCK1 6093 Rock1 19877 TRCN0000022899GCAGAAATAATGAATCGCAAA 454 2.0 ROCK1 6093 Rock1 19877 ND000566ATCAAGATCAGATCGTGGAAG 455 2.2 ROCK1 6093 Rock1 19877 TRCN0000361453TTCAATTGGTGAGGCATAAAT 456 2.3 ROCK1 6093 Rock1 19877 TRCN0000022903GCAGTGTCTCAAATTGAGAAA 457 4.1 ROCK1 6093 Rock1 19877 TRCN0000361455TGTGGGATGCTACCTGATAAA 458 4.4 ROCK1 6093 Rock1 19877 TRCN0000361522CTACAGGTAGATTAGATTAAT 459 5.6 ROCK1 6093 Rock1 19877 TRCN0000361521CAACTTTCTAAGCAGATATAA 460 6.5 ROCK1 6093 Sbf1 77980 ND000571CAGTATGTTACTCGTAAGAAG 461 0.2 SBF1 6305 Sbf1 77980 TRCN0000081099GCAGTATGTTACTCGTAAGAA 462 0.4 SBF1 6305 Sbfl 77980 ND000575TGCTAAGTTGTTTCTAGAACC 463 0.8 SBF1 6305 Sbf1 77980 ND000570CGATACTATGACCACCGAATG 464 0.8 SBF1 6305 Sbfl 77980 TRCN0000081101CGAGAGGAATCCACCAACTTT 465 0.9 SBF1 6305 Sbf1 77980 TRCN0000081102GCGATACTATGACCACCGAAT 466 1.5 SBF1 6305 Sbf1 77980 ND000578CTAACTTATTGTGGTGTCATG 467 1.5 SBF1 6305 Sbf1 77980 ND000574TCTTGCTGGACTCTGATTATG 468 1.6 SBF1 6305 Sbf1 77980 ND000572GGCTAGATGAGGGCACAATTC 469 2.2 SBF1 6305 Sbf1 77980 ND000573GAAGACAACACGTCGCGTTTA 470 3.1 SBF1 6305 Sbf1 77980 ND000577TACGGAATTGCATCTCCTATG 471 3.2 SBF1 6305 Sbf1 77980 TRCN0000081098CACGCGGACATCTATGACAAA 472 4.8 SBF1 6305 Sbf1 77980 ND000579TTACCACATACCGCGTCATCT 473 5.6 SBF1 6305 Sbfl 77980 TRCN0000081100CCCTACAGCAATGTGTCCAAT 474 6.0 SBF1 6305 Sbfl 77980 ND000576GACTTTGTCGTCCGCATGATG 475 6.9 SBF1 6305 Smad2 17126 ND000208AGATCAGTGGGACACAACAGG 476 0.4 SMAD2 4087 Smad2 17126 TRCN0000039336TGGTGTTCAATCGCATACTAT 477 1.0 SMAD2 4087 Smad2 17126 ND000205GTAATTACATCCCAGAAACAC 478 1.1 SMAD2 4087 Smad2 17126 TRCN0000089334CGGTTAGATGAGCTTGAGAAA 479 1.2 SMAD2 4087 Smad2 17126 TRCN0000089333CCAGTAGTAGTGCCTGAAGTA 480 1.2 SMAD2 4087 Smad2 17126 ND000207TAACCCGAATGTGCACCATAA 481 1.2 SMAD2 4087 Smad2 17126 ND000199CCCAACTGTAACCAGAGATAC 482 1.4 SMAD2 4087 Smad2 17126 TRCN0000089335CCACTGTAGAAATGACAAGAA 483 1.5 SMAD2 4087 Smad2 17126 ND000200CCTCCGTCGTAGTATTCATGT 484 1.9 SMAD2 4087 Smad2 17126 ND000201GCCAGTGGTGAAGAGACTTCT 485 1.9 SMAD2 4087 Smad2 17126 ND000203CTCGGCACACGGAGATTCTAA 486 6.7 SMAD2 4087 Smad2 17126 ND000204GACAGTATCCCAAAGGTTATT 487 7.1 SMAD2 4087 Smad2 17126 ND000202GAGTGCGCTTGTATTACATAG 488 7.1 SMAD2 4087 Smad2 17126 TRCN0000089337CTAAGTGATAGTGCAATCTTT 489 19.3 SMAD2 4087 Smad2 17126 ND000206TGCCTAAGTGATAGTGCAATC 490 30.3 SMAD2 4087 Socs1 12703 ND000214TETCGAGCTGCTGGAGCACTA 491 0.6 SOCS1 8651 Socs1 12703 ND000219TCGAGCTGCTGGAGCACTACG 492 1.2 SOCS1 8651 Socs1 12703 TRCN0000231240TCGCCAACGGAACTGCTTCTT 493 1.4 SOCS1 8651 Socs1 12703 ND000218ACTTCTGGCTGGAGACCTCAT 494 1.5 SOCS1 8651 Socs1 12703 TRCN0000067420GCGAGACCTTCGACTGCCTTT 495 1.7 SOCS1 8651 Socs1 12703 TRCN0000067418CGACACTCACTTCCGCACCTT 496 1.8 SOCS1 8651 Socs1 12703 ND000220CTACCTGAGTTCCTTCCCCTT 497 1.8 SOCS1 8651 Socs1 12703 TRCN0000231238TTCCGCTCCCACTCCGATTAC 498 1.8 SOCS1 8651 Socs1 12703 TRCN0000231241TAACCCGGTACTCCGTGACTA 499 1.9 SOCS1 8651 Socs1 12703 ND000216TACTCCGTGACTACCTGAGTT 500 2.4 SOCS1 8551 Socs1 12703 ND000211CCTCCGCTCCCACTCCGATTA 501 2.6 SOCS1 8651 Socs1 12703 TRCN0000067422GCGCGACAGTCGCCAACGGAA 502 2.7 SOCS1 8651 Socs1 12703 TRCN0000231239TGGACGCCTGCGGCTTCTATT 503 2.9 SOCS1 8651 Socs1 12703 TRCN0000067419CGCATCCCTCTTAACCCGGTA 504 3.4 SOCS1 8651 Socs1 12703 ND000212TACATATTCCCAGTATCTTTG 505 3.6 SOCS1 8651 Socs1 12703 TRCN0000231242GCGCCTTATTATTTCTTATTA 506 4.1 SOCS1 8651 Socs1 12703 TRCN0000067421CCGTGACTACCTGAGTTCCTT 507 5.8 SOCS1 8651 Socs1 12703 ND000215GGAGGGTCTCTGGCTTCATTT 508 7.8 SOCS1 8651 Socs1 12703 ND000213TTCGCGCTCAGCGTGAAGATG 509 8.4 SOCS1 8651 Socs1 12703 ND000217ATCCCTUTAACCCGGTACTC 510 8.5 SOCS1 8651 Socs3 12702 ND000222CGAGAAGATTCCGCTGGTACT 511 0.3 SOCS3 9021 Socs3 12702 TRCN0000067472GCTGCAGGAGAGCGGATTCTA 512 0.4 SOCS3 9021 Socs3 12702 TRCN0000231180GGCTAGGAGACTCGCCTTAAA 513 0.7 SOCS3 9021 Socs3 12702 TRCN0000067468GCTAGGAGACTCGCCTTAAAT 514 0.8 SOCS3 9021 Socs3 12702 ND000227GAGAGCTTACTACATCTATTC 515 0.9 SOCS3 9021 Socs3 12702 ND000221GGGAGTTCCTGGATCAGTATG 516 1.0 SOCS3 9021 Socs3 12702 TRCN0000067470CAAGAGAGGTTACTACATCTA 517 1.1 SOCS3 9021 Socs3 12702 TRCN0000231179CAGTATGATGCTCCACTTTAA 518 1.2 SOCS3 9021 Socs3 12702 ND000223CAAGCTGGTGCACCACTACAT 519 1.3 SOCS3 9021 Socs3 12702 ND000224ACCTGGACTCCTATGAGAAAG 520 1.4 SOCS3 9021 Socs3 12702 TRCN0000067471CTTCTTCACGTTGAGCGTCAA 521 1.6 SOCS3 9021 Socs3 12702 ND000228TCGGGAGTTCCTGGATCAGTA 522 1.7 SOCS3 9021 Socs3 12702 ND000226TGCAGGAGAGCGGATTCTACT 523 1.9 SOCS3 9021 Socs3 12702 ND000225CCTGGTGGGACAATACCTTTG 524 3.3 SOCS3 9021 Socs3 12702 TRCN0000067469GATCAGTATGATGCTCCACTT 525 4.6 SOCS3 9021 Socs3 12702 TRCN0000231176TCTTCACGTTGAGCGTCAAGA 526 4.7 SOCS3 9021 Socs3 12702 TRCN0000231177CGCTTCGACTGTGTACTCAAG 527 4.9 SOCS3 9021 Socs3 12702 ND000229GGAGCAAAAGGGTCAGAGGGG 528 5.3 SOCS3 9021 Stk17b 98267 ND000590AGTGGGACTTTGGAAGCTTGT 529 0.3 STK17B 9262 Stk17b 98267 ND000597CATCTGGACTGACTCGGAAAT 530 0.5 STK17B 9262 Stk17b 98267 ND000596ATGCTGCGGGTGGAGAAATTT 531 0.6 STK17B 9262 Stk17b 98267 ND000588TATCTGAATATTTCTCAAGTG 532 0.6 STK17B 9262 Stk17b 98267 ND000593TTTACCTGAGTTAGCCGAAAT 533 0.7 STK17B 9262 Stk17b 98267 ND000589GTTAACTCATACATCACCATT 534 1.1 STK17B 9262 Stk17b 98267 ND000594CCTATACCATAACTCTATTAC 535 1.3 STK17B 9262 Stk17b 98267 ND000592CTCAACTATGATCCCATTACC 536 1.3 STK17B 9262 Stk17b 98267 ND000591AGACCTCCAAGTCCTCCTGTA 537 1.4 STK17B 9262 Stk17b 98267 TRCN0000024255GCTGTGGTTAGACAATGTATA 538 1.6 STK17B 9262 Stk17b 98267 ND000595TATTGGCATAATAGCGTATAT 539 3.6 STK17B 9262 Stk17b 98267 TRCN0000024256GCTTGTTTCATCCTGAGGAAA 540 4.0 STK17B 9262 Stk17b 98267 TRCN0000024258TCCTCAACTATGATCCCATTA 541 4.2 STK17B 9262 Stk17b 98267 TRCN0000024254GCAGAAGCTAAGGACGAATTT 542 4.4 STK17B 9262 Stk17b 98267 TRCN0000024257CAGAATAACATTGTTCACCTT 543 6.4 STK17B 9262 Tnk1 83813 ND000599TGCCCAGCGCAGACTTAATGA 544 0.3 TNK1 8711 Tnk1 83813 TRCN0000023704CGTGACACTCTGGGAAATGTT 545 0.6 TNK1 8711 Tnk1 83813 ND000602GTGTCCCACCATATCTCATCC 546 0.7 TNK1 8711 Tnk1 83813 ND000600AGTAGCAATACCGGATCACTG 547 0.7 TNK1 8711 Tnk1 83813 TRCN0000023706GCGGGAAGTATCTGTCATGAT 548 0.8 TNK1 8711 Tnk1 83813 ND000603AGAGGATGCGAGGCATTTCCA 549 1.1 TNK1 8711 Tnk1 83813 ND000601GGACAGAGAGAAGGCAACGTT 550 1.1 TNK1 8711 Tnk1 83813 TRCN0000361891AGAATTGGGTGTACAAGATAC 551 1.3 TNK1 8711 Tnk1 83813 TRCN0000023707CCACCTATTATCTGCAACTCT 552 1.6 TNK1 8711 Tnk1 83813 TRCN0000023705GCCTCTGATGTGTGGATGTTT 553 1.7 TNK1 8711 Tnk1 83813 TRCN0000361890TGCAGAGGATGCGAGGCATTT 554 1.8 TNK1 8711 Tnk1 83813 TRCN0000361889TGGCGTGACACTCTGGGAAAT 555 2.0 TNK1 8711 Tnk1 83813 TRCN0000023708CAGACTTAATGAAGCCCTGAA 556 5.2 TNK1 8711 Tnk1 83813 TRCN0000361892GTGTTGTACATCGAGGGTTAT 557 5.2 TNK1 8711 Tnk1 83813 ND000398CCAGAACTTCGGCGTACAAGA 558 7.6 TNK1 8711 Trpm7 58800 ND000607GAAGTATCAGCGGTATCATTT 559 0.4 TRPM7 54822 Trpm7 58800 TRCN0000274774ATGGATTGTTATCGCTTATAT 560 0.7 TRPM7 54822 Trpm7 58800 ND000606GCTTGGAAAGGGTCTTATTAA 561 0.9 TRPM7 54822 Trpm7 58800 ND000608ATTGAATCCCTTGAGCAAATT 562 0.9 TRPM7 54872 Trpm7 58800 TRCN0000274712CCTTATCAAACCCTATTGAAT 563 1.1 TRPM7 54827 Trpm7 58800 TRCN0000274773CCAAAGATCAAGAACCCATTT 564 1.2 TRPM7 54822 Trpm7 58800 ND000604TAGAGGTAATGTTCTCATTGA 565 1.2 TRPM7 54822 Trpm7 58800 ND000610ACCGGATTGGTTACGAGATAG 566 1.5 TRPM7 54822 Trpm7 58800 TRCN0000274772ACCTGGTGCAGGACCATTAAC 567 1.7 TRPM7 54822 Trpm7 58800 ND000605TAGACTTTCTAGCCGTAAATC 568 2.9 TRPM7 54822 Trpm7 58800 TRCN0000274711CTAGACTTTCTAGCCGTAAAT 569 3.1 TRPM7 54822 Trpm7 58800 TRCN0000023957CCTCAGGATGAGTCATCAGAT 570 3.5 TRPM7 54822 Trpm7 58800 TRCN0000023956CCTGGTATAAGGTCATATTAA 571 4.9 TRPM7 54822 Trpm7 58800 TRCN0000023955GCTCAGAATCTTATTGATGAT 572 5.3 TRPM7 54822 Trpm7 58800 ND000609GCCCTAACAGTAGATACATTG 573 5.9 TRPM7 54822 Vamp7 20955 TRCN0000115068CTTACTCACATGGCAATTATT 574 0.6 VAMP7 6845 Vamp7 20955 TRCN0000380436GCACAACTGAAGCATCACTCT 575 0.8 VAMP7 6845 Vamp7 20955 TRCN0000336075GCACAAGTGGATGAACTGAAA 576 0.9 VAMP7 6845 Vamp7 20955 TRCN0000336077TTACGGTTCAAGAGCACAAAC 577 1.0 VAMP7 6845 Vamp7 20955 TRCN0000380733TAAGAGCCTAGACAAAGTGAT 578 1.0 VAMP7 6845 Vamp7 20955 ND000255AGCCATGTGTATGAAGAATAT 579 1.2 VAMP7 6845 Vamp7 20955 ND000258TCCAGGAGCCCATACAAGTAA 580 1.4 VAMP7 6845 Vamp7 20955 ND000255ATAAACTAACTTACTCACATG 581 1.5 VAMP7 6845 Vamp7 20955 TRCN0000336014GCCGCCACATTTCGTTGTAAA 582 1.8 VAMP7 6845 Vamp7 20955 TRCN0000353419GCACTTCCTTATGCTATGAAT 583 1.9 VAMP7 6845 Vamp7 20955 TRCN0000115066GCCTTAAGATATGCAATGTTA 584 2.2 VAMP7 6845 Vamp7 20955 ND000257CTGAAAGGAATAATGGTCAGA 585 4.0 VAMP7 6845 Vamp7 20955 ND000239CTCCTTGTAAATGATACACAA 586 9.8 VAMP7 6845 Vamp7 20955 TRCN0000353291CTTTGCCTGTCATATAGTTTG 587 10.5 VAMP7 6845 Vamp7 20955 TRCN0000115069TCGAGCCATGTGTATGAAGAA 588 11.3 VAMP7 6845 Yes1 22612 ND000617ATCCCTAGCAATTACGTAGTG 589 0.5 YES1 7525 Yes1 22612 TRCN0000339152TGGTTATATCCCTAGCAATTA 590 0.5 YES1 7525 Yes1 22612 ND000614TATGCTTCACTCGGCATGTTT 591 0.6 YES1 7525 Yes1 22612 ND000616ATTCCAGATACGGTTACTCAA 592 0.6 YES1 7525 Yes1 22612 ND000613TTTAAGAAGGGTGAACGATTT 593 0.7 YES1 7525 Yes1 22612 ND000612CACGACCAGAGCTCAGTTTGA 594 0.8 YES1 7525 Yes1 22612 ND000615CAGGTATGGTAAACCGTGAAG 599 0.8 YES1 7525 Yes1 22612 ND000611GGAGTGGAACATGCTACAGTT 596 1.0 YES1 7525 Yes1 22612 ND000618CCTCATECTCAGTGGTGTCAA 597 2.6 YES1 7525 Yes1 22612 ND000619TCGAGAATCATTGCGACTAGA 598 2.8 YES1 7525 Yes1 22612 TRCN0000339083CCAGGTACAATGATGCCAGAA 599 2.8 YES1 7525 Yes1 22612 TRCN0000339150GCGGAAAGATTACTTCTGAAT 600 3.9 YES1 7525 Yes1 22612 TRCN0000023616GCTGCTCTGTATGGTCGATTT 601 4.1 YES1 7525 Yes1 22612 TRCN0000023618CCTTGTATGATTATGAAGCTA 602 5.4 YES1 7525 Yes1 22612 TRCN0000023617GCCAGTCATTATGGAGTGGAA 603 9.7 YES1 7525

shRNAs demonstrating an at least ≥3 shRNAs fold enrichment in tumorrelative to spleen indicate amore active target sequence region.

In some aspects, the nucleic acids of the compositions encode the shRNAsequences targeting the human Ppp2r2d and Cblb sequences provided inTable 2a.

TABLE 2a # Gene Human shRNA Target Sequence 1 Ppp2r2dCCCGCACCAGTGCAACGTGTT (SEQ ID NO: 636) 2 Ppp2r2d TCATAGTGGGCGGTACATGAT(SEQ ID NO: 637) 3 Ppp2r2d GAGAATTAATTTATGGCACTT (SEQ ID NO: 638) 4Ppp2r2d CCATTTAGGATCACGGCGCTA (SEQ ID NO: 639) 5 Ppp2r2dATAGTGATCATGAAACATATC (SEQ ID NO: 375) 6 Ppp2r2d GCCACCAATAACTTGTACATA(SEQ ID NO: 640) 7 Ppp2r2d CGGTTCGGATAGCGCCATCAT (SEQ ID NO: 641) 8Ppp2r2d TCATTTCCACCGTTGAGTTTA (SEQ ID NO: 642) 9 Ppp2r2dATGCTCACACATATCATATAA (SEQ ID NO: 643) 1 Cblb CGGGCAATAAGACTCTTTAA(SEQ ID NO: 644) 2 Cblb TGCCCAGGTCCAGTTCCATTTC (SEQ ID NO: 645) 3 CblbTCCTGATTTAACTGGATTATG (SEQ ID NO: 646) 4 Cblb ATCAAACATCCCTGACTTAAG(SEQ ID NO: 647) 5 Cblb CTACACCTCATGACCATATAA (SEQ ID NO: 648) 6 CblbTACACCTCATGACCATATAAA (SEQ ID NO: 649) 7 Cblb TCAGTGAGAATGAGTACTTTA(SEQ ID NO: 650) 8 Cblb CCTGACTTAAGCATATATTTA (SEQ ID NO: 651) 9 CblbTCTACATTGATAGCCTTATGA (SEQ ID NO: 652)

In other embodiments, the disclosure provides isolated nucleic acidsencoding shRNA sequences complementary to a Ppp2r2d target sequenceidentical to at least 12, at least 15, at least 20, or at least 25contiguous nucleotides set forth in SEQ ID NO: 372, 373, 374, 375, 376,377, 378, 378, 379, 380, 381, 382, 383, 384, 385, or 386.

In other embodiments, the disclosure provides isolated nucleic acidsencoding a shRNA comprising a sequence complementary to a human Pp2r2dsequence that corresponds to a murine target sequence set forth in SEQID NO: 372, 373, 374, 375, 376, 377, 378, 378, 379, 380, 381, 382, 383,384, 385, or 386.

In other embodiments, the disclosure provides isolated nucleic acidsencoding shRNA sequences complementary to a Eif2ak3 target sequenceidentical to at least 12, at least 15, at least 20, or at least 25contiguous nucleotides set forth in SEQ ID NO: 133, 134, 135, 136, 137,138, 139, 140, 141, 142, 143, 144, 145, 146 or 147.

In other embodiments, the disclosure provides isolated nucleic acidsencoding a shRNA comprising a sequence complementary to a human Eifak3sequence that corresponds to a murine target sequence set forth in SEQID NO: 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145,146 or 147.

In other embodiments, the disclosure provides isolated nucleic acidsencoding shRNA sequences complementary to an Arhgap5 target sequenceidentical to at least 12, at least 15, at least 20, or at least 25contiguous nucleotides set forth in SEQ ID NO: 32, 33, 34, 35, 36, 37,38, 39, 40, 41, or 42.

In other embodiments, the disclosure provides isolated nucleic acidsencoding a shRNA comprising a sequence complementary to a human Arhgap5sequence that corresponds to a murine target sequence set forth in SEQID NO: 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, or 42.

In other embodiments, the disclosure provides isolated nucleic acidsencoding shRNA sequences complementary to a Smad2 target sequenceidentical to at least 12, at least 15, at least 20, or at least 25contiguous nucleotides set forth in SEQ ID NO: 476, 477, 478, 479, 480,481, 482, 483, 484, 485, 486, 487, 488, 489, or 490.

In other embodiments, the disclosure provides isolated nucleic acidsencoding a shRNA comprising a sequence complementary to a human Smad2sequence that corresponds to a murine target sequence set forth in SEQID NO: 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488,489, or 490.

In other embodiments, the disclosure provides isolated nucleic acidsencoding shRNA sequences complementary to an Akap81 target sequenceidentical to at least 12, at least 15, at least 20, or at least 25contiguous nucleotides set forth in SEQ ID NO: 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, or 15.

In other embodiments, the disclosure provides isolated nucleic acidsencoding a shRNA comprising a sequence complementary to a human Akap81sequence that corresponds to a murine target sequence set forth in SEQID NO: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.

In other embodiments, the disclosure provides isolated nucleic acidsencoding shRNA sequences complementary to a Rbks target sequenceidentical to at least 12, at least 15, at least 20, or at least 25contiguous nucleotides set forth in SEQ ID NO: 431, 432, 433, 434, 435,436, 437, 438, 439, 440, 441, 442, 443, 444, or 445.

In other embodiments, the disclosure provides isolated nucleic acidsencoding a shRNA comprising a sequence complementary to a human Rbkssequence that corresponds to a murine target sequence set forth in SEQID NO: 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443,444, or 445.

In other embodiments, the disclosure provides isolated nucleic acidsencoding shRNA sequences complementary to an Egr2 target sequenceidentical to at least 12, at least 15, at least 20, or at least 25contiguous nucleotides set forth in SEQ ID NO: 118, 119, 120, 121, 122,123, 124, 125, 126, 127, 128, 129, 130, 131, or 132.

In other embodiments, the disclosure provides isolated nucleic acidsencoding a shRNA comprising a sequence complementary to a human Egr2sequence that corresponds to a murine target sequence set forth in SEQID NO: 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130,131, or 132.

In other embodiments, the disclosure provides isolated nucleic acidsencoding shRNA sequences complementary to a Dgka target sequenceidentical to at least 12, at least 15, at least 20, or at least 25contiguous nucleotides set forth in SEQ ID NO: 88, 89, 90, 91, 92, 93,94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108,109, 110, 111, 112, 113, 114, 115, 116 or 117.

In other embodiments, the disclosure provides isolated nucleic acidsencoding a shRNA comprising a sequence complementary to a human Dgkasequence that corresponds to a murine target sequence set forth in SEQID NO: 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102,103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116 or117.

In other embodiments, the disclosure provides isolated nucleic acidsencoding shRNA sequences complementary to a Cblb target sequenceidentical to at least 12, at least 15, at least 20, or at least 25contiguous nucleotides set forth in SEQ ID NO: 58, 59, 60, 61, 62, 63,64, 65, 66, 67, 68, 69, 70, 71, or 72.

In other embodiments, the disclosure provides isolated nucleic acidsencoding a shRNA comprising a sequence complementary to a human Cblbsequence that corresponds to a murine target sequence set forth in SEQID NO: 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, or 72.

In other embodiments, the disclosure provides isolated nucleic acidsencoding shRNA sequences complementary to a Mdfic target sequenceidentical to at least 12, at least 15, at least 20, or at least 25contiguous nucleotides set forth in SEQ ID NO: 285, 286, 287, 288, 289,290, 291, 292, 293, 294, 295, 296, 297, 298, or 299.

In other embodiments, the disclosure provides isolated nucleic acidsencoding a shRNA comprising a sequence complementary to a human Mdficsequence that corresponds to a murine target sequence set forth in SEQID NO: 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297,298, or 299.

In other embodiments, the disclosure provides isolated nucleic acidsencoding shRNA sequences complementary to an Entpd1 target sequenceidentical to at least 12, at least 15, at least 20, or at least 25contiguous nucleotides set forth in SEQ ID NO: 148, 149, 150, 151, 152,153, 154, 155, 156, 157, 158, 159, 160, 161, or 162.

In other embodiments, the disclosure provides isolated nucleic acidsencoding a shRNA comprising a sequence complementary to a human Entpd1sequence that corresponds to a murine target sequence set forth in SEQID NO: 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160,161, or 162.

In other embodiments, the disclosure provides isolated nucleic acidsencoding shRNA sequences complementary to a Vamp7 target sequenceidentical to at least 12, at least 15, at least 20, or at least 25contiguous nucleotides set forth in SEQ ID NO: 574, 575, 576, 577, 578,579, 580, 581, 582, 583, 584, 585, 586, or 587.

In other embodiments, the disclosure provides isolated nucleic acidsencoding a shRNA comprising a sequence complementary to a humanVamp7sequence that corresponds to a murine target sequence set forth inSEQ ID NO: 574, 575, 576, 577, 578, 579, 580, 581, 582, 583, 584, 585,586, or 587.

In other embodiments, the disclosure provides isolated nucleic acidsencoding shRNA sequences complementary to a Hipk1 target sequenceidentical to at least 12, at least 15, at least 20, or at least 25contiguous nucleotides set forth in SEQ ID NO. 208, 209, 210, 211, 212,213, 214, 215, 216, 217, 218, 219, 220, 221, or 222.

In other embodiments, the disclosure provides isolated nucleic acidsencoding a shRNA comprising a sequence complementary to a human Hipk1sequence that corresponds to a murine target sequence set forth in SEQID NO: 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220,221, or 222.

In other embodiments, the disclosure provides isolated nucleic acidsencoding shRNA sequences complementary to a Nuak2 target sequenceidentical to at least 12, at least 15, at least 20, or at least 25contiguous nucleotides set forth in SEQ ID NO: 315, 316, 317, 318, 319,320, 321, 322, 323, 324, 325, 326, 327, 328, or 329.

In other embodiments, the disclosure provides isolated nucleic acidsencoding a shRNA comprising a sequence complementary to a human Nuak2sequence that corresponds to a murine target sequence set forth in SEQID NO: 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327,328, or 329.

In other embodiments, the disclosure provides isolated nucleic acidsencoding shRNA sequences complementary to an Alk target sequenceidentical to at least 12, at least 15, at least 20, or at least 25contiguous nucleotides set forth in SEQ ID NO: 16, 17, 18, 19, 20, 21,22, 23, 24, 25, 26, 27, 28, 29, 30, or 31.

In other embodiments, the disclosure provides isolated nucleic acidsencoding a shRNA comprising a sequence complementary to a human Alksequence that corresponds to a murine target sequence set forth in SEQID NO: 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or31.

In other embodiments, the disclosure provides isolated nucleic acidsencoding shRNA sequences complementary to a Pdzk1ip1target sequenceidentical to at least 12, at least 15, at least 20, or at least 25contiguous nucleotides set forth in SEQ ID NO: 330, 331, 332, 333, 334,335, 336, 337, 338, 339, 340, or 341.

In other embodiments, the disclosure provides isolated nucleic acidsencoding a shRNA comprising a sequence complementary to a human Pdzk1ip1sequence that corresponds to a murine target sequence set forth in SEQID NO: 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, or 341.

In other embodiments, the disclosure provides isolated nucleic acidsencoding shRNA sequences complementary to a Blvrb target sequenceidentical to at least 12, at least 15, at least 20, or at least 25contiguous nucleotides set forth in SEQ ID NO: 52, 53, 54, 55, 56 or 57.

In other embodiments, the disclosure provides isolated nucleic acidsencoding a shRNA comprising a sequence complementary to a human Blvrbthat corresponds to a murine target sequence set forth in SEQ ID NO: 52,53, 54, 55, 56 or 57.

In other embodiments, the disclosure provides isolated nucleic acidsencoding shRNA sequences complementary to a Cdkn2a target sequenceidentical to at least 12, at least 15, at least 20, or at least 25contiguous nucleotides set forth in SEQ ID NO: 83, 84, 85, 86 or 87.

In other embodiments, the disclosure provides isolated nucleic acidsencoding a shRNA comprising a sequence complementary to a human Cdkn2athat corresponds to a murine target sequence set forth in SEQ ID NO: 83,84, 85, 86 or 87.

In other embodiments, the disclosure provides isolated nucleic acidsencoding shRNA sequences complementary to a F11r target sequenceidentical to at least 12, at least 15, at least 20, or at least 25contiguous nucleotides set forth in SEQ ID NO: 175, 176 or 177.

In other embodiments, the disclosure provides isolated nucleic acidsencoding a shRNA comprising a sequence complementary to a human F11rthat corresponds to a murine target sequence set forth in SEQ ID NO:175, 176 or 177.

In other embodiments, the disclosure provides isolated nucleic acidsencoding shRNA sequences complementary to a Fyn target sequenceidentical to at least 12, at least 15, at least 20, or at least 25contiguous nucleotides set forth in SEQ ID NO: 187, 191 or 192.

In other embodiments, the disclosure provides isolated nucleic acidsencoding a shRNA comprising a sequence complementary to a human Fyn thatcorresponds to a murine target sequence set forth in SEQ ID NO: 187, 191or 192.

In other embodiments, the disclosure provides isolated nucleic acidsencoding shRNA sequences complementary to a Grk6 target sequenceidentical to at least 12, at least 15, at least 20, or at least 25contiguous nucleotides set forth in SEQ ID NO: 204, 205, 206 or 207.

In other embodiments, the disclosure provides isolated nucleic acidsencoding a shRNA comprising a sequence complementary to a human Grk6that corresponds to a murine target sequence set forth in SEQ ID NO:204, 205, 206 or 207.

In other embodiments, the disclosure provides isolated nucleic acidsencoding shRNA sequences complementary to an Inpp5b target sequenceidentical to at least 12, at least 15, at least 20, or at least 25contiguous nucleotides set forth in SEQ ID NO: 232, 234, 235, 236 or237.

In other embodiments, the disclosure provides isolated nucleic acidsencoding a shRNA comprising a sequence complementary to a human Inpp5bthat corresponds to a murine target sequence set forth in SEQ ID NO:232, 234, 235, 236 or 237.

In other embodiments, the disclosure provides isolated nucleic acidsencoding shRNA sequences complementary to an Impk target sequenceidentical to at least 12, at least 15, at least 20, or at least 25contiguous nucleotides set forth in SEQ ID NO: 248, 249, 250, 251 or252.

In other embodiments, the disclosure provides isolated nucleic acidsencoding a shRNA comprising a sequence complementary to a human Impkthat corresponds to a murine target sequence set forth in SEQ ID NO:248, 249, 250, 251 or 252.

In other embodiments, the disclosure provides isolated nucleic acidsencoding shRNA sequences complementary to a Jun target sequenceidentical to at least 12, at least 15, at least 20, or at least 25contiguous nucleotides set forth in SEQ ID NO: 263, 264, 265, 266, 267,268 or 269.

In other embodiments, the disclosure provides isolated nucleic acidsencoding a shRNA comprising a sequence complementary to a human Jun thatcorresponds to a murine target sequence set forth in SEQ ID NO: 263,264, 265, 266, 267, 268 or 269.

In other embodiments, the disclosure provides isolated nucleic acidsencoding shRNA sequences complementary to a Mast2 target sequenceidentical to at least 12, at least 15, at least 20, or at least 25contiguous nucleotides set forth in SEQ ID NO: 281, 282, 283 or 284.

In other embodiments, the disclosure provides isolated nucleic acidsencoding a shRNA comprising a sequence complementary to a human Mast2that corresponds to a murine target sequence set forth in SEQ ID NO:281, 282, 283 or 284. In other embodiments, the disclosure providesisolated nucleic acids encoding shRNA sequences complementary to a Nptxrtarget sequence identical to at least 12, at least 15, at least 20, orat least 25 contiguous nucleotides set forth in SEQ ID NO: 311, 312, 313or 314.

In other embodiments, the disclosure provides isolated nucleic acidsencoding a shRNA comprising a sequence complementary to a human Nptxrthat corresponds to a murine target sequence set forth in SEQ ID NO:311, 312, 313 or 314.

In other embodiments, the disclosure provides isolated nucleic acidsencoding shRNA sequences complementary to a Pkd1 target sequenceidentical to at least 12, at least 15, at least 20, or at least 25contiguous nucleotides set forth in SEQ ID NO: 351, 352, 353, 354, 355or 356.

In other embodiments, the disclosure provides isolated nucleic acidsencoding a shRNA comprising a sequence complementary to a human Pkd1that corresponds to a murine target sequence set forth in SEQ ID NO:351, 352, 353, 354, 355 or 356.

In other embodiments, the disclosure provides isolated nucleic acidsencoding shRNA sequences complementary to a Ppm1g target sequenceidentical to at least 12, at least 15, at least 20, or at least 25contiguous nucleotides set forth in SEQ ID NO: 367, 368, 369, 370 or371.

In other embodiments, the disclosure provides isolated nucleic acidsencoding a shRNA comprising a sequence complementary to a human Ppm1gthat corresponds to a murine target sequence set forth in SEQ ID NO:367, 368, 369, 370 or 371.

In other embodiments, the disclosure provides isolated nucleic acidsencoding shRNA sequences complementary to a Ppp3cc target sequenceidentical to at least 12, at least 15, at least 20, or at least 25contiguous nucleotides set forth in SEQ ID NO: 399, 400 or 401.

In other embodiments, the disclosure provides isolated nucleic acidsencoding a shRNA comprising a sequence complementary to a human Ppp3ccthat corresponds to a murine target sequence set forth in SEQ ID NO:399, 400 or 401.

In other embodiments, the disclosure provides isolated nucleic acidsencoding shRNA sequences complementary to a Prkab2 target sequenceidentical to at least 12, at least 15, at least 20, or at least 25contiguous nucleotides set forth in SEQ ID NO: 414, 415 or 416.

In other embodiments, the disclosure provides isolated nucleic acidsencoding a shRNA comprising a sequence complementary to a human Prkab2that corresponds to a murine target sequence set forth in SEQ ID NO:414, 415 or 416.

In other embodiments, the disclosure provides isolated nucleic acidsencoding shRNA sequences complementary to a Ptpn2 target sequenceidentical to at least 12, at least 15, at least 20, or at least 25contiguous nucleotides set forth in SEQ ID NO: 426, 427, 428, 429 or430.

In other embodiments, the disclosure provides isolated nucleic acidsencoding a shRNA comprising a sequence complementary to a human Ptpn2that corresponds to a murine target sequence set forth in SEQ ID NO:426, 427, 428, 429 or 430.

In other embodiments, the disclosure provides isolated nucleic acidsencoding shRNA sequences complementary to a Rock1 target sequenceidentical to at least 12, at least 15, at least 20, or at least 25contiguous nucleotides set forth in SEQ ID NO: 457, 458, 459 or 460.

In other embodiments, the disclosure provides isolated nucleic acidsencoding a shRNA comprising a sequence complementary to a human Rock1that corresponds to a murine target sequence set forth in SEQ ID NO:457, 458, 459 or 460.

In other embodiments, the disclosure provides isolated nucleic acidsencoding shRNA sequences complementary to a Sbf1 target sequenceidentical to at least 12, at least 15, at least 20, or at least 25contiguous nucleotides set forth in SEQ ID NO: 470, 471, 472, 473, 474or 475.

In other embodiments, the disclosure provides isolated nucleic acidsencoding a shRNA comprising a sequence complementary to a human Sbf1that corresponds to a murine target sequence set forth in SEQ ID NO:470, 471, 472, 473, 474 or 475.

In other embodiments, the disclosure provides isolated nucleic acidsencoding shRNA sequences complementary to a Socs1 target sequenceidentical to at least 12, at least 15, at least 20, or at least 25contiguous nucleotides set forth in SEQ ID NO: 504, 505, 506, 507, 508,509 or 510.

In other embodiments, the disclosure provides isolated nucleic acidsencoding a shRNA comprising a sequence complementary to a human Socs1that corresponds to a murine target sequence set forth in SEQ ID NO:504, 505, 506, 507, 508, 509 or 510.

In other embodiments, the disclosure provides isolated nucleic acidsencoding shRNA sequences complementary to a Socs3 target sequenceidentical to at least 12, at least 15, at least 20, or at least 25contiguous nucleotides set forth in SEQ ID NO: 524, 525, 526, 527 or528.

In other embodiments, the disclosure provides isolated nucleic acidsencoding a shRNA comprising a sequence complementary to a human Socs3that corresponds to a murine target sequence set forth in SEQ ID NO:524, 525, 526, 527 or 528.

In other embodiments, the disclosure provides isolated nucleic acidsencoding shRNA sequences complementary to a Stk17b target sequenceidentical to at least 12, at least 15, at least 20, or at least 25contiguous nucleotides set forth in SEQ ID NO: 539, 540, 541, 542 or543.

In other embodiments, the disclosure provides isolated nucleic acidsencoding a shRNA comprising a sequence complementary to a human Stk17bthat corresponds to a murine target sequence set forth in SEQ ID NO:539, 540, 541, 542 or 543.

In other embodiments, the disclosure provides isolated nucleic acidsencoding shRNA sequences complementary to a Tnk1 target sequenceidentical to at least 12, at least 15, at least 20, or at least 25contiguous nucleotides set forth in SEQ ID NO: 556, 557 or 558.

In other embodiments, the disclosure provides isolated nucleic acidsencoding a shRNA comprising a sequence complementary to a human Tnk1that corresponds to a murine target sequence set forth in SEQ ID NO:556, 557 or 558.

In other embodiments, the disclosure provides isolated nucleic acidsencoding shRNA sequences complementary to a Trpm7 target sequenceidentical to at least 12, at least 15, at least 20, or at least 25contiguous nucleotides set forth in SEQ ID NO: 569, 570, 571, 572 or573.

In other embodiments, the disclosure provides isolated nucleic acidsencoding a shRNA comprising a sequence complementary to a human Trpm7that corresponds to a murine target sequence set forth in SEQ ID NO:569, 570, 571, 572 or 573.

In other embodiments, the disclosure provides isolated nucleic acidsencoding shRNA sequences complementary to a Yes1 target sequenceidentical to at least 12, at least 15, at least 20, or at least 25contiguous nucleotides set forth in SEQ ID NO: 600, 601, 602 or 603.

In other embodiments, the disclosure provides isolated nucleic acidsencoding a shRNA comprising a sequence complementary to a human Yes1that corresponds to a murine target sequence set forth in SEQ ID NO:600, 601, 602 or 603. In any embodiment, a human sequence thatcorresponds to a murine target sequence is a sequence which perfectlycorresponds to the human gene sequence, and for example, can have none,1, 2, 3 or 4 nucleotide mismatches with the at least 12, at least 15, atleast 20, or at least 25 contiguous nucleotides of the selected murinetarget sequence.

An isolated nucleic acid can be, for example, a DNA molecule, providedone of the nucleic acid sequences normally found immediately flankingthat DNA molecule in a naturally-occurring genome is removed or absent.Thus, an isolated nucleic acid includes, without limitation, a DNAmolecule that exists as a separate molecule (e.g., a chemicallysynthesized nucleic acid, cDNA, or genomic DNA fragment produced by PCRor restriction endonuclease treatment) independent of other sequences aswell as DNA that is incorporated into a vector, an autonomouslyreplicating plasmid, a virus (e.g., a retrovirus, lentivirus,adenovirus, adeno-associated virus, or herpes virus), or into thegenomic DNA of a prokaryote or eukaryote. In addition, an isolatednucleic acid can include an engineered nucleic acid such as arecombinant DNA molecule that is part of a hybrid or fusion nucleicacid. A nucleic acid existing among hundreds to millions of othernucleic acids within, for example, cDNA libraries or genomic libraries,or gel slices containing a genomic DNA restriction digest, is not to beconsidered an isolated nucleic acid.

In calculating percent sequence identity, two sequences are aligned andthe number of identical matches of nucleotides or amino acid residuesbetween the two sequences is determined. The number of identical matchesis divided by the length of the aligned region (i.e., the number ofaligned nucleotides or amino acid residues) and multiplied by 100 toarrive at a percent sequence identity value. It will be appreciated thatthe length of the aligned region can be a portion of one or bothsequences up to the full-length size of the shortest sequence. It alsowill be appreciated that a single sequence can align with more than oneother sequence and hence, can have different percent sequence identityvalues over each aligned region. It is noted that the percent identityvalue is usually rounded to the nearest integer. For example, 78.1%,78.2%, 78.3%, and 78.4% are rounded down to 78%, while 78.5%, 78.6%,78.7%, 78.8%, and 78.9% are rounded up to 79%. It is also noted that thelength of the aligned region is always an integer.

As used herein, the term “percent sequence identity” refers to thedegree of identity between any given query sequence and a subjectsequence. A percent identity for any query nucleic acid or amino acidsequence, e.g., a transcription factor, relative to another subjectnucleic acid or amino acid sequence can be determined as follows.

As used herein, the term “complementary nucleotide sequence,” also knownas an “antisense sequence,” refers to a sequence of a nucleic acid thatis completely complementary to the sequence of a “sense” nucleic acidencoding a protein (e.g., complementary to the coding strand of adouble-stranded cDNA molecule or complementary to an mRNA sequence).Herein, nucleic acid molecules are provided that comprise a sequencecomplementary to at least about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24,or 25 nucleotides or an entire gene coding strand, or to only a portionthereof.

As used herein, the term “correspond to a nucleotide sequence” refers toa nucleotide sequence of a nucleic acid encoding an identical sequence.In some instances, when antisense nucleotides (nucleic acids) or siRNA's(small inhibitory RNA) hybridize to a target sequence a particularantisense or small inhibitory RNA (siRNA) sequence is substantiallycomplementary to the target sequence, and thus will specifically bind toa portion of an mRNA encoding polypeptide. As such, typically thesequences of those nucleic acids will be highly complementary to themRNA target sequence, and will have no more than 1, 2, 3, 4, 5, 6, 7, 8,9, or 10 base mismatches throughout the sequence. In many instances, itmay be desirable for the sequences of the nucleic acids to be exactmatches, i.e. be completely complementary to the sequence to which theoligonucleotide specifically binds, and therefore have zero mismatchesalong the complementary stretch. Highly complementary sequences willtypically bind quite specifically to the target sequence region of themRNA and will therefore be highly efficient in reducing, and/or eveninhibiting the translation of the target mRNA sequence into polypeptideproduct.

As used herein, the term “vector” refers to any viral or non-viralvector, as well as any plasmid, cosmid, phage or binary vector in doubleor single stranded linear or circular form that may or may not be selftransmissible or mobilizable, and that can transform prokaryotic oreukaryotic host cells either by integration into the cellular genome orwhich can exist extrachromosomally (e.g., autonomous replicating plasmidwith an origin of replication). Any vector known in the art isenvisioned for use in the practice of this invention.

Vectors can be viral vectors or non-viral vectors. Should viral vectorsbe used, it is preferred the viral vectors are replication defective,which can be achieved for example by removing all viral nucleic acidsthat encode for replication. A replication defective viral vector willstill retain its infective properties and enters the cells in a similarmanner as a replicating adenoviral vector, however once admitted to thecell a replication defective viral vector does not reproduce ormultiply. Vectors also encompass liposomes and nanoparticles and othermeans to deliver DNA molecule to a cell.

The term “viral vectors” refers to the use of viruses, orvirus-associated vectors as carriers of a nucleic acid construct into acell. Constructs may be integrated and packaged into non-replicating,defective viral genomes like Adenovirus, Adeno-associated virus (AAV),or Herpes simplex virus (HSV) or others, including retroviral andlentiviral vectors, for infection or transduction into cells. The vectormay or may not be incorporated into the cell's genome.

“Encoding” refers to the inherent property of specific sequences ofnucleotides in a polynucleotide, such as a gene, a cDNA, or an mRNA, toserve as templates for synthesis of other polymers and macromolecules inbiological processes having either a defined sequence of nucleotides(i.e., rRNA, tRNA and mRNA) or a defined sequence of amino acids and thebiological properties resulting therefrom, Thus, a gene encodes aprotein if transcription and translation of mRNA corresponding to thatgene produces the protein in a cell or other biological system, Both thecoding strand, the nucleotide sequence of which is identical to the mRNAsequence and is usually provided in sequence listings, and thenon-coding strand, used as the template for transcription of a gene orcDNA, can be referred to as encoding the protein or other product ofthat gene or cDNA.

The term “expression” as used herein is defined as the transcriptionand/or translation of a particular nucleotide sequence driven by itspromoter.

Vectors capable of directing the expression of genes to which they areoperatively linked are referred to herein as “expression vectors”. Thus,an “Expression vector” is a specialized vector comprising a recombinantpolynucleotide comprising expression control sequences operativelylinked to a nucleotide sequence to be expressed. An expression vectorcomprises sufficient cis-acting elements for expression; other elementsfor expression can be supplied by the host cell or in an in vitroexpression system. Expression vectors include all those known in theart, such as cosmids, plasmids (e.g., naked or contained in liposomes)and viruses (e.g., lentiviruses, retroviruses, adenoviruses, andadeno-associated viruses) that incorporate the recombinantpolynucleotide.

In some aspects, the disclosure provides modified cells that harborvectors capable of expressing the shRNA described herein and furthermodified to express a CAR. In one aspect the shRNA and the CAR areexpressed on the same vector. In another aspect, the shRNA and the CARare expressed on separate vectors.

In some embodiments, the modified cells described herein areimmunoresponsive cells. In some aspects, the immunoresponsive cellsexpress at least one of an antigen-recognizing receptor. In any aspect,the immunoresponsive cells express at least one of an tumor specificantigen-recognizing receptor. In some aspects, tumor cell antigenspecific T cells, NKT cells, TIL, CTL cells or other immunoresponsivecells are used. Non-limiting examples of immunoresponsive cells includeT cells, such as, for example, αβ-TCR+ T cells (e.g., CD8+ T cells orCD4+ T cells) γδ-TCR+ T cells, tumor-infiltrating lymphocytes (TIL),Natural Killer T cells (NKT), a cytotoxic T lymphocytes (CTL), and a CD4T cells.

Compositions comprising the immunoresponsive cells of the invention(e.g., T cells, NKT cells, TILs, CTL cells, or their progenitors) can beprovided systemically or directly to a subject for the treatment of acancer. In one embodiment, cells of the invention are directly injectedinto an organ of interest (e.g., an organ affected by a cancer).Alternatively, compositions comprising genetically modifiedimmunoresponsive cells are provided indirectly to the organ of interest,for example, by administration into the circulatory system (e.g., thetumor vasculature). Expansion and differentiation agents can be providedprior to, during or after administration of the cells to increaseproduction of T cells, NKT cells, TILs, CTL cells in vitro or in vivo.

The modified immunoresponsive cells can be administered in anyphysiologically acceptable vehicle, normally intravascularly, althoughthey may also be introduced into bone or other convenient site where thecells may find an appropriate site for regeneration and differentiation(e.g., thymus). Usually, at least 1×10⁵ cells will be administered,eventually reaching 1×10¹⁰, or more. Immunoresponsive cells of theinvention can comprise a purified population of cells. Those skilled inthe art can readily determine the percentage of genetically modifiedimmunoresponsive cells in a population using various well-known methods,such as fluorescence activated cell sorting (FACS). Preferable ranges ofpurity in populations comprising genetically modified immunoresponsivecells are about 50 to about 55%, about 55 to about 60%, and about 65 toabout 70%. More preferably the purity is about 70 to about 75%, about 75to about 80%, about 80 to about 85%; and still more preferably thepurity is about 85 to about 90%, about 90 to about 95%, and about 95 toabout 100%. Dosages can be readily adjusted by those skilled in the art(e.g., a decrease in purity may require an increase in dosage).

The cells can be introduced by injection, catheter, or the like. Ifdesired, factors can also be included, including, but not limited to,interleukins, e.g. IL-2, IL-3, IL-6, and IL-11, as well as the otherinterleukins, the colony stimulating factors, such as G-, M- and GM-CSF,interferons, e.g. .gamma.-interferon and erythropoietin.

Compositions of the invention include pharmaceutical compositionscomprising the immunoresponsive cells of the invention or theirprogenitors and a pharmaceutically acceptable carrier. Administrationcan be autologous or heterologous. For example, immunoresponsive cells,or progenitors can be obtained from one subject, and administered to thesame subject or a different, compatible subject.

Chimeric Antigen Receptors

In some instances, the invention provides chimeric antigen receptors(CARs) comprising an antigen binding domain directed to a tumor cellantigen. A CAR is an artificially constructed hybrid protein orpolypeptide containing an extracellular portion that recognizes a tumorcell antigen (e.g., the antigen binding domains of an antibody (scFv)and a cyloplasmic signaling domain derived from the T cell receptor andcostimulatory domain. (Kalos M, et al., Sci Transl Med. 2011 Aug. 10;3(95)) Kalos et al. describes the generation of CAR T cells that targetCD19 and demonstrates the CAR modified T-cells mediated potent antitumoreffect in chronic lymphocytic leukemia patients. Characteristics of CARsinclude their ability to redirect T-cell specificity and reactivitytoward a selected target in a non-MHC-restricted manner, exploiting theantigen-binding properties of monoclonal antibodies. The CAR-modifiedT-cells have the potential to replicate in vivo and long termpersistence allows for sustained tumor control and obviate the need forrepeated infusions of antibody. (Kalos M, et al., Sci Transl Med. 2011Aug. 10; 3(95)) The non-MHC-restricted antigen recognition gives T cellsexpressing CARs the ability to recognize antigen independent of antigenprocessing, thus bypassing a major mechanism of tumor escape. Moreover,when expressed in T-cells, CARs advantageously do not dimerize withendogenous T cell receptor (TCR) alpha and beta chains. CAR-modified Tcells are described in detail in WO2012/079000 and WO2012/09999 and inMilone et al. 2009 Mol. Ther. 17:1453.

A CAR combines the binding site of a molecule that recognizes an antigenbeing targeted (i.e., an “antigen binding domain”) with one or moredomains of conventional immune receptors responsible for initiatingsignal transduction that leads to lymphocyte activation (e.g., the“stimulatory domain” or “signaling domain”).

In some embodiments, the binding portion used is derived from thestructure of the Fab (antigen binding) fragment of a monoclonal antibody(mAb) that has high affinity for the tumor antigen being targeted.Because the Fab is the product of two genes, the corresponding sequencesare usually combined via a short linker fragment that allows theheavy-chain to fold over the light-chain derived peptides into theirnative configuration, creating a single-chain fragment variable (scFv)region.

Fv or (scFv) antibody fragments comprise the VH and VL domains ofantibody, wherein these domains are present in a single polypeptidechain. Generally the Fv polypeptide further comprises a polypeptidelinker between the VH and VL domains, which enables the scFv to form thedesired structure for antigen binding.

In some embodiments, the binding portion used is derived from acytoplasmic signaling domain derived from T cell receptor andcostimulatory molecules.

In some embodiments, the signaling portion of CARs contains usually theintracellular domains of the zeta (ξ) chain of the TCR/CD3 complex²⁵ or,less commonly, of the gamma (γ) chain of the immunoglobulin receptorFceRI^(26, 27) or the CD3-epsilon (ε) chain,²⁸ with the transmembraneregion being derived from the same molecule.

In some aspects, the CARs comprise an antigen binding domain, atransmembrane domain, a stimulatory domain, and a co-stimulatory domain.Further embodiments of the invention provide related nucleic acids,recombinant expression vectors, host cells, populations of cells,antibodies, or antigen binding portions thereof, and pharmaceuticalcompositions relating to the CARs of the invention.

In one aspect, the antigen binding domain binds to a tumor cell antigen.The term “tumor cell antigen” or “tumor antigen” as used herein refersto any polypeptide expressed by a tumor that is capable of inducing animmune response. Non-limiting examples of tumor antigens include, forexample, prostate-specific membrane antigen (PSMA), CarcinoembryonicAntigen (CEA), CD19, CD20, CD22, ROR1, mesothelin, CD333/IL3Ra, c-Met,Glycolipid F77, EGFRvIII, GD-2, NY-ESO-1 TCR, ERBB2, BIRC5, CEACAM5,WDR46, BAGE, CSAG2, DCT, MAGED4, GAGE1, GAGE2, GAGE3, GAGE4, GAGE5,GAGE6, GAGE7, GAGE8, IL13RA2, MAGEA1, MAGEA2, MAGEA3, MAGEA4, MAGEA6,MAGEA9, MAGEA10, MAGEA12, MAGEB1, MAGEB2, MAGEC2, TP53, TYR, TYRP1,SAGE1, SYCP1, SSX2, SSX4, KRAS, PRAME, NRAS, ACTN4, CTNNB1, CASP8,CDC27, CDK4, EEF2, FN1, HSPA1B, LPGAT1, ME1, HHAT, TRAPPC1, MUM3, MYO1B,PAPOLG, OS9, PTPRK, TPI1, ADFP, AFP, AIM2, ANXA2, ART4, CLCA2, CPSF1,PPIB, EPHA2, EPHA3, FGF5, CA9, TERT, MGAT5, CEL, F4.2, CAN, ETV6, BIRC7,CSF1, OGT, MUC1, MUC2, MUM1, CTAG1A, CTAG2, CTAG, MRPL28, FOLH1, RAGE,SFMBT1, KAAG1, SART1, TSPYL1, SART3, SOX10, TRG, WT1, TACSTD1, SILV,SCGB2A2, MC1R, MLANA, GPR143, OCA2, KLK3, SUPT7L, ARTC1, BRAF, CASP5,CDKN2A, UBXD5, EFTUD2, GPNMB, NFYC, PRDX5, ZUBR1, SIRT2, SNRPD1,HERV-K-MEL, CXorf61, CCDC110, VENTXP1, SPA17, KLK4, ANKRD30A, RAB38,CCND1, CYPIB1, MDM2, MMP2, ZNF395, RNF43, SCRN1, STEAP1, 707-AP, TGFBR2,PXDNL, AKAP13, PRTN3, PSCA, RHAMM, ACPP, ACRBP, LCK, RCVRN, RPS2,RPL10A, SLC45A3, BCL2L1, DKK1, ENAH, CSPG4, RGS5, BCR, BCR-ABL, ABL-BCR,DEK, DEK-CAN, ETV6-AML1, LDLR-FUT, NPM1-ALK1, PML-RARA, SYT-SSX1,SYT-SSX2, FLT3, ABL1, AML1, LDLR, FUT1, NPM1, ALK, PML1, RARA, SYT,SSX1, MSLN, UBE2V1, HNRPL, WHSC2, EIF4EBP1, WNK2, OAS3, BCL-2, MCL1,CTSH, ABCC3, BST2, MFGE8, TPBG, FMOD, XAGE1, RPSA, COTL1, CALR3, PA2G4,EZH2, FMNL1, HPSE, APC, UBE2A, BCAP31, TOP2A, TOP2B, ITGB8, RPA1, ABI2,CCNI, CDC2, SEPT2, STAT1, LRP1, ADAM17, JUP, DDR1, ITPR2, HMOX1, TPM4,BAAT, DNAJC8, TAPBP, LGALS3BP, PAGE4, PAK2, CDKN1A, PTHLH, SOX2, SOX11,TRPM8, TYMS, ATIC, PGK1, SOX4, TOR3A, TRGC2, BTBD2, SLBP, EGFR, IER3,TTK, LY6K, IGF2BP3, GPC3, SLC35A4, HSMD, H3F3A, ALDH1A1, MFI2, MMP14,SDCBP, PARP12, MET, CCNB1, PAX3-FKHR, PAX3, FOXO1, XBP1, SYND1, ETV5,HSPA1A, HMHA1, TRIM68 and any combination thereof.

The present invention relates generally to the use of T cellsgenetically modified to stably express a shRNA of the invention and adesired CAR. T cells expressing a CAR are generally referred to as CAR Tcells. T cells expressing a CAR are referred to herein as CAR T cells orCAR modified T cells. Preferably, the cell can be genetically modifiedto stably express an antibody binding domain on its surface, conferringnovel antigen specificity that is MHC independent. In some instances,the T cell is genetically modified to stably express a CAR that combinesan antigen recognition domain of a specific antibody with anintracellular stimulatory domain (e.g., signaling domain). Thus, inaddition to an antigen binding domain the CAR can include theintracellular domains of the zeta (chain of the TCR/CD3 complex, thegamma (γ) chain of the immunoglobulin receptor FcεRI26, 27 or theCD3-epsilon (ε) chain. The CAR can also include a transmembrane regionbeing from the same molecules or other type I transmembrane proteinssuch as CD4, CD8 and CD28.

In one embodiment, the CAR of the invention comprises an extracellulardomain having an antigen recognition domain, a transmembrane domain, anda cytoplasmic domain.

In one embodiment, the transmembrane domain that naturally is associatedwith one of the domains in the CAR is used. In another embodiment, thecytoplasmic domain can be designed to comprise a stimulatory domain anda costimulatory domain.

A CAR can include intracytoplasmatic portion of co-stimulatorymolecules, such as CD28, CD134/OX40, CD137/4-1BB, Lck, ICOS or DAPO.

The disclosure also relates to a strategy of Adoptive cell therapy(ACT). ACT is a procedure in which therapeutic lymphocytes areadministered to patients in order to treat cancer. This approach entailsthe ex vivo generation of tumor specific T cell lymphocytes and infusingthem to patients. In addition to the lymphocyte infusion the host may bemanipulated in other ways which support the take of the T cells andtheir immune response, for example, preconditioning the host (withradiation or chemotherapy) and administration of lymphocyte growthfactors (such as IL-2). One method for generating such tumor specificlymphocytes involves the expansion of antigen specific T cells.

In one embodiment, the invention provides generating T cells expressinga shRNA of the invention and a desired CAR directed to a tumor antigen.The modified T cells can be generated by introducing a vector (e.g.,plasmid, lentiviral vector, retroviral vector, adenoviral vector,adeno-associated viral vector) encoding both 1) an shRNA capable ofreducing expression of a target gene described herein and 2) a desiredCAR into the cells. The modified T cells of the invention are able toreplicate in vivo resulting in long term persistence that can lead totumor control.

In one aspect, the disclosure provides methods of treating cancercomprising administering a composition capable of silencing genes thatinhibit T cell function. In one embodiment, the methods relate toadministering T cell expressing a shRNA of the invention and a desiredCAR directed to a tumor antigen. In one aspect the T cell to beadministered comprises a vector encoding a shRNA of the invention and adesired CAR directed to a tumor antigen.

Pharmaceutical Formulations

In some instances, therapeutic compositions disclosed herein caninclude, in addition to the tumor targeting T cells, compounds, drugs,and/or agents used for the treatment of cancer. Such compounds, drugs,and/or agents can include, for example, chemotherapy drugs, smallmolecule drugs or antibodies that stimulate the immune response to agiven cancer. In other instances, therapeutic compositions can include,for example, one or more small molecule inhibitors that silence,reduces, eliminates, knocks down, knocks out, or decreases theexpression and/or activity of genes selected from the group consistingof Ppp2r2d, Eif2ak3, Arhgap5, Smad2, Akap81, Rbks, Egr2, Dgka, Cblb,Mdfic, Entpd1, Dgkz, Vamp7, Hipk1, Nuak2, Alk, Pdzk1ip1, Inpp5b, Socs1,Jun, Nptxr, Socs3, F11r, Fyn, Ypel2, Pkd1, Grk6, Cdkn2a, Sbf1, Ipmk,Rock1, Stk17b, Mast2, Pdp1, Yes1, Met, Ppm1g, Blvrb, Tnk1, Prkab2, Trpm7and Ppp3cc. Accordingly, the invention provides one or more inhibitorsof Ppp2r2d, Eif2ak3, Arhgap5, Smad2, Akap81, Rbks, Egr2, Dgka, Cblb,Mdfic, Entpd1, Dgkz, Vamp7, Hipk1, Nuak2, Alk, Pdzk1ip1, Inpp5b, Socs1,Jun, Nptxr, Socs3, F11r, Fyn, Ypel2, Pkd1, Grk6, Cdkn2a, Sbf1, Ipmk,Rock1, Stk17b, Mast2, Pdp1, Yes1, Met, Ppm1g, Blvrb, Tnk1, Prkab2, Trpm7or Ppp3cc.

In one aspect, the invention provides one or more inhibitors of Ppp2r2d.

In another aspect, the invention provides one or more inhibitors ofEif2ak3.

In another aspect, the invention provides one or more inhibitors ofArhgap5.

In another aspect, the invention provides one or more inhibitors ofSmad2.

In another aspect, the invention provides one or more inhibitors ofAkap81.

In another aspect, the invention provides one or more inhibitors ofRbks.

In another aspect, the invention provides one or more inhibitors ofEgr2.

In another aspect, the invention provides one or more inhibitors ofDgka.

In another aspect, the invention provides one or more inhibitors ofCblb.

In another aspect, the invention provides one or more inhibitors ofMap3k3.

In another aspect, the invention provides one or more inhibitors vMdfic.

In another aspect, the invention provides one or more inhibitors ofEntpd1.

In another aspect, the invention provides one or more inhibitors ofDgkz.

In another aspect, the invention provides one or more inhibitors ofVamp7.

In another aspect, the invention provides one or more inhibitors ofNuak2.

In another aspect, the invention provides one or more inhibitors ofHipk1.

In another aspect, the invention provides one or more inhibitors of Alk.In one embodiment, the inhibitor of Alk includes, for example, forexample CH5424802 (Hoffmann-La Roche), LDK378 (Novartis), Crizotinib andPF-02341066 (Pfizer) or AP26113 (Ariad Pharmaceuticals).

In another aspect, the invention provides one or more inhibitors ofPdzk1ip1.

In some instances, therapeutic compositions can include, for example,cytokines, chemokines and other biologic signaling molecules, tumorspecific vaccines, cellular cancer vaccines (e.g., GM-CSF transducedcancer cells), tumor specific monoclonal antibodies, autologous andallogeneic stem cell rescue (e.g., to augment graft versus tumoreffects), other therapeutic antibodies, molecular targeted therapies,anti-angiogenic therapy, infectious agents with therapeutic intent (suchas tumor localizing bacteria) and gene therapy.

In some instances, therapeutic compositions disclosed herein can beformulated for use as or in pharmaceutical compositions. Suchcompositions can be formulated or adapted for administration to asubject via any route, e.g., any route approved by the Food and DrugAdministration (FDA). Exemplary methods are described in the FDA's CDERData Standards Manual, version number 004 (which is available atfda.give/cder/dsm/DRG/drg00301.htm).

In some instances, pharmaceutical compositions can include an effectiveamount of one or more peptides. The terms “effective amount” and“effective to treat,” as used herein, refer to an amount or aconcentration of one or more peptides for a period of time (includingacute or chronic administration and periodic or continuousadministration) that is effective within the context of itsadministration for causing an intended effect or physiological outcome.

The pharmaceutical compositions of this invention may contain anyconventional non-toxic pharmaceutically-acceptable carriers, adjuvantsor vehicles. In some cases, the pH of the formulation may be adjustedwith pharmaceutically acceptable acids, bases or buffers to enhance thestability of the formulated compound or its delivery form.

Methods

In some instances, methods can include selection of a human subject whohas or had a condition or disease (e.g., cancer). In some instances,suitable subjects include, for example, subjects who have or had acondition or disease but that resolved the disease or an aspect thereof,present reduced symptoms of disease (e.g., relative to other subjects(e.g., the majority of subjects) with the same condition or disease),and/or that survive for extended periods of time with the condition ordisease (e.g., relative to other subjects (e.g., the majority ofsubjects) with the same condition or disease), e.g., in an asymptomaticstate (e.g., relative to other subjects (e.g., the majority of subjects)with the same condition or disease).

The term “subject,” as used herein, refers to any animal. In someinstances, the subject is a mammal. In some instances, the term“subject”, as used herein, refers to a human (e.g., a man, a woman, or achild). Samples for use in the methods can include serum samples, e.g.,obtained from the selected subject.

In some instances, subject selection can include obtaining a sample froma subject (e.g., a candidate subject) and testing the sample for anindication that the subject is suitable for selection. In someinstances, the subject can be confirmed or identified, e.g. by a healthcare professional, as having had or having a condition or disease. Insome instances, exhibition of a positive immune response towards acondition or disease can be made from patient records, family history,and/or detecting an indication of a positive immune response. In someinstances multiple parties can be included in subject selection. Forexample, a first party can obtain a sample from a candidate subject anda second party can test the sample. In some instances, subjects can beselected and/or referred by a medical practitioner (e.g., a generalpractitioner). In some instances, subject selection can includeobtaining a sample from a selected subject and storing the sample and/orusing the in the methods disclosed herein. Samples can include, forexample, cells or populations of cells.

Methods of Use

In some embodiments, the disclosure provides methods for increasing theimmune response in a subject in need thereof. The disclosure providestherapies that are particularly useful for the treatment of subjectshaving cancer. In some instances, the disclosure provides methods oftreatment that include administering to a subject a compositiondisclosed herein.

Provided herein are methods for treating and/or preventing cancer orsymptoms of cancer in a subject comprising administering to the subjecta therapeutically effective amount of a composition capable of silencinggenes that inhibit T cell function (e.g., an immunoresponsive T cellexpressing a shRNA of the invention and a desired CAR directed to atumor antigen). In some cases the T cell is derived from the patient tobe treated and has been modified to express the CAR and an shRNA thatreduces expression of a target gene described herein.

In some embodiments, the cancer is a carcinoma, sarcomas,adenocarcinoma, lymphoma, leukemia, etc., including solid and lymphoidcancers, kidney, breast, lung, bladder, colon, ovarian, prostate,pancreas, stomach, brain, head and neck, skin, uterine, testicular,glioma, esophagus, and liver cancer, including hepatocarcinoma,lymphoma, including B-acute lymphoblastic lymphoma, non-Hodgkin'slymphomas (e.g., Burkitt's, Small Cell, and Large Cell lymphomas) andHodgkin's lymphoma, leukemia (including AML, ALL, and CML), and multiplemyeloma. In some embodiments, the cancer is melanoma. In someembodiments, the cancer is a plasma cell malignancy, for example,multiple myeloma (MM) or pre-malignant condition of plasma cells. Insome embodiments the subject has been diagnosed as having a cancer or asbeing predisposed to cancer.

As used herein, “cancer” refers to human cancers and carcinomas,sarcomas, adenocarcinomas, lymphomas, leukemias, etc., including solidand lymphoid cancers, kidney, breast, lung, bladder, colon, ovarian,prostate, pancreas, stomach, brain, head and neck, skin, uterine,testicular, glioma, esophagus, and liver cancer, includinghepatocarcinoma, lymphoma, including B-acute lymphoblastic lymphoma,non-Hodgkin's lymphomas (e.g., Burkitt's, Small Cell, and Large Celllymphomas) and Hodgkin's lymphoma, leukemia (including AML, ALL, andCML), and multiple myeloma.

The term “anti-tumor effect” as used herein, refers to a biologicaleffect which can be manifested by a decrease in tumor volume, a decreasein the number of tumor cells, a decrease in the number of metastases, anincrease in life expectancy, or amelioration of various physiologicalsymptoms associated with the cancerous condition. An “anti-tumor effect”can also be manifested by the ability of the peptides, polynucleotides,cells and antibodies of the invention in prevention of the occurrence oftumor in the first place.

The terms “treat” or “treating,” as used herein, refers to partially orcompletely alleviating, inhibiting, ameliorating, and/or relieving thedisease or condition from which the subject is suffering. In someinstances, treatment can result in the continued absence of the diseaseor condition from which the subject is suffering.

In general, methods include selecting a subject at risk for or with acondition or disease. In some instances, the subject's condition ordisease can be treated with a pharmaceutical composition disclosedherein. For example, in some instances, methods include selecting asubject with cancer, e.g., wherein the subject's cancer can be treatedby increasing T cell accumulation and infiltration within the tumor.

In some instances, treatments methods can include a singleadministration, multiple administrations, and repeating administrationas required for the prophylaxis or treatment of the disease or conditionfrom which the subject is suffering. In some instances treatment methodscan include assessing a level of disease in the subject prior totreatment, during treatment, and/or after treatment. In some instances,treatment can continue until a decrease in the level of disease in thesubject is detected.

Following administration, the subject can be evaluated to detect,assess, or determine their level of disease. In some instances,treatment can continue until a change (e.g., reduction) in the level ofdisease in the subject is detected.

Upon improvement of a patient's condition (e.g., a change (e.g.,decrease) in the level of disease in the subject), a maintenance dose ofa compound, composition or combination of this invention may beadministered, if necessary. Subsequently, the dosage or frequency ofadministration, or both, may be reduced, as a function of the symptoms,to a level at which the improved condition is retained. Patients may,however, require intermittent treatment on a long-term basis upon anyrecurrence of disease symptoms.

It is also within the scope of the present invention to combine any ofthe methods and any of the compositions disclosed herein with one ormore therapeutic agents. A therapeutic agent includes, but is notlimited to, small molecules, peptides, antibodies, ribozymes, antisenseoligonucleotides, chemotherapeutic agents and radiation.

It is also within the scope of the present invention to combine any ofthe methods and any of the compositions disclosed herein withconventional cancer therapies and various drugs in order to enhance theefficacy of such therapies through either reducing the doses/toxicity ofconventional therapies and/or to increase the sensitivity ofconventional therapies. One conventional therapy is the use of radiationtherapy. Another conventional therapy is the use of chemotherapeuticdrugs that can be divided into: alkylating agents, antimetabolites,anthracyclines, plant alkaloids, topoisomerase inhibitors, andantitumour agents. All of these drugs affect cell division or DNAsynthesis and function in some way. Other conventional cancer therapiesare agents that do not directly interfere with DNA. Examples of suchagents for which to combine with the present invention may include forexample “small-molecule” drugs that block specific enzymes involved incancer cell growth. Monoclonal antibodies, cancer vaccines, angiogenesisinhibitors, and gene therapy are targeted therapies that can also becombined with the compositions and methods disclosed herein because theyalso interfere with the growth of cancer cells.

Methods of Screening Test Compounds

Included herein are methods for screening test compounds, e.g.,polypeptides, polynucleotides, inorganic or organic large or smallmolecule test compounds, to identify agents useful in the treatment ofcancer e.g., test compounds that silence, reduces, eliminates, knocksdown, knocks out, modulates, or decreases the expression and/or activityof genes selected from the group consisting of Ppp2r2d, Eif2ak3,Arhgap5, Smad2, Akap81, Rbks, Egr2, Dgka, Cblb, Mdfic, Entpd1, Dgkz,Vamp7, Hipk1, Nuak2, Alk, Pdzk1ip1, Inpp5b, Socs1, Jun, Nptxr, Socs3,F11r, Fyn, Ypel2, Pkd1, Grk6, Cdkn2a, Sbf1, Ipmk, Rock1, Stk17b, Mast2,Pdp1, Yes1, Met, Ppm1g, Blvrb, Tnk1, Prkab2, Trpm7 and Ppp3cc.

As used herein, “small molecules” refers to small organic or inorganicmolecules of molecular weight below about 3,000 Daltons. In general,small molecules useful for the invention have a molecular weight of lessthan 3,000 Daltons (Da). The small molecules can be, e.g., from at leastabout 100 Da to about 3,000 Da (e.g., between about 100 to about 3,000Da, about 100 to about 2500 Da, about 100 to about 2,000 Da, about 100to about 1,750 Da, about 100 to about 1,500 Da, about 100 to about 1,250Da, about 100 to about 1,000 Da, about 100 to about 750 Da, about 100 toabout 500 Da, about 200 to about 1500, about 500 to about 1000, about300 to about 1000 Da, or about 100 to about 250 Da).

The test compounds can be, e.g., natural products or members of acombinatorial chemistry library. A set of diverse molecules should beused to cover a variety of functions such as charge, aromaticity,hydrogen bonding, flexibility, size, length of side chain,hydrophobicity, and rigidity. Combinatorial techniques suitable forsynthesizing small molecules are known in the art, e.g., as exemplifiedby Obrecht and Villalgordo, Solid-Supported Combinatorial and ParallelSynthesis of Small-Molecular-Weight Compound Libraries,Pergamon-Elsevier Science Limited (1998), and include those such as the“split and pool” or “parallel” synthesis techniques, solid-phase andsolution-phase techniques, and encoding techniques (see, for example,Czarnik, Curr. Opin. Chem. Bio. 1:60-6 (1997)). In addition, a number ofsmall molecule libraries are commercially available. A number ofsuitable small molecule test compounds are listed in U.S. Pat. No.6,503,713, incorporated herein by reference in its entirety.

Libraries screened using the methods of the present invention cancomprise a variety of types of test compounds. A given library cancomprise a set of structurally related or unrelated test compounds. Insome embodiments, the test compounds are peptide or peptidomimeticmolecules. In some embodiments, the test compounds are nucleic acids.

In some embodiments, the test compounds and libraries thereof can beobtained by systematically altering the structure of a first testcompound, e.g., a first test compound that is structurally similar to aknown natural binding partner of the target polypeptide, or a firstsmall molecule identified as capable of binding the target polypeptide,e.g., using methods known in the art or the methods described herein,and correlating that structure to a resulting biological activity, e.g.,a structure-activity relationship study. As one of skill in the art willappreciate, there are a variety of standard methods for creating such astructure-activity relationship. Thus, in some instances, the work maybe largely empirical, and in others, the three-dimensional structure ofan endogenous polypeptide or portion thereof can be used as a startingpoint for the rational design of a small molecule compound or compounds.For example, in one embodiment, a general library of small molecules isscreened, e.g., using the methods described herein.

In some embodiments, a test compound is applied to a test sample, e.g.,a cell or living tissue or organ, e.g., an eye, and one or more effectsof the test compound is evaluated. In a cultured or primary cell forexample, the ability of the test compound to silence, reduces,eliminates, knocks down, knocks out, modulates, or decreases theexpression and/or activity of genes selected from the group consistingof Ppp2r2d, Eif2ak3, Arhgap5, Smad2, Akap81, Rbks, Egr2, Dgka, Cblb,Mdfic, Entpd1, Dgkz, Vamp7, Hipk1, Nuak2, Alk, Pdzk1ip1, Inpp5b, Socs1,Jun, Nptxr, Socs3, F11r, Fyn, Ypel2, Pkd1, Grk6, Cdkn2a, Sbf1, Ipmk,Rock1, Stk17b, Mast2, Pdp1, Yes1, Met, Ppm1g, Blvrb, Tnk1, Prkab2, Trpm7and Ppp3cc.

In some embodiments, the test sample is, or is derived from (e.g., asample taken from) an in vivo model of a disorder as described herein.For example, an animal model, e.g., a rodent such as a rat, can be used.

Methods for evaluating each of these effects are known in the art. Forexample, ability to modulate expression of a protein can be evaluated atthe gene or protein level, e.g., using quantitative PCR or immunoassaymethods. In some embodiments, high throughput methods, e.g., protein orgene chips as are known in the art (see, e.g., Ch. 12, Genomics, inGriffiths et al., Eds. Modern genetic Analysis, 1999, W. H. Freeman andCompany; Ekins and Chu, Trends in Biotechnology, 1999, 17:217-218;MacBeath and Schreiber, Science 2000, 289(5485):1760-1763; Simpson,Proteins and Proteomics: A Laboratory Manual, Cold Spring HarborLaboratory Press; 2002; Hardiman, Microarrays Methods and Applications:Nuts & Bolts, DNA Press, 2003), can be used to detect an effect onPpp2r2d, Eif2ak3, Arhgap5, Smad2, Akap81, Rbks, Egr2, Dgka, Cblb, Mdfic,Entpd1, Dgkz, Vamp7, Hipk1, Nuak2, Alk, Pdzk1ip1, Inpp5b, Socs1, Jun,Nptxr, Socs3, F11r, Fyn, Ypel2, Pkd1, Grk6, Cdkn2a, Sbf1, Ipmk, Rock1,Stk17b, Mast2, Pdp1, Yes1, Met, Ppm1g, Blvrb, Tnk1, Prkab2, Trpm7 andPpp3cc activity or gene expression.

A test compound that has been screened by a method described herein anddetermined to silence, reduces, eliminates, knocks down, knocks out, ordecreases the expression and/or activity of genes selected from thegroup consisting of Ppp2r2d, Eif2ak3, Arhgap5, Smad2, Akap81, Rbks,Egr2, Dgka, Cblb, Mdfic, Entpd1, Dgkz, Vamp7, Hipk1, Nuak2, Alk,Pdzk1ip1, Inpp5b, Socs1, Jun, Nptxr, Socs3, F11r, Fyn, Ypel2, Pkd1,Grk6, Cdkn2a, Sbf1, Ipmk, Rock1, Stk17b, Mast2, Pdp1, Yes1, Met, Ppm1g,Blvrb, Tnk1, Prkab2, Trpm7 and Ppp3cc, can be considered a candidatecompound. A candidate compound that has been screened, e.g., in an invivo model of a disorder, e.g., cancer, and determined to have adesirable effect on the disorder, e.g., on one or more symptoms of thedisorder, can be considered a candidate therapeutic agent. Candidatetherapeutic agents, once screened in a clinical setting, are therapeuticagents. Candidate compounds, candidate therapeutic agents, andtherapeutic agents can be optionally optimized and/or derivatized, andformulated with physiologically acceptable excipients to formpharmaceutical compositions.

Thus, test compounds identified as “hits” (e.g., test compounds thatinhibiting immunosuppressive pathways used by tumor cells to inactivateand/or suppress immune cells) in a first screen can be selected andsystematically altered, e.g., using rational design, to optimize bindingaffinity, avidity, specificity, or other parameter. Such optimizationcan also be screened for using the methods described herein. Thus, inone embodiment, the invention includes screening a first library ofcompounds using a method known in the art and/or described herein,identifying one or more hits in that library, subjecting those hits tosystematic structural alteration to create a second library of compoundsstructurally related to the hit, and screening the second library usingthe methods described herein.

EXAMPLES

The invention is further described in the following examples, which donot limit the scope of the invention described in the claims.

Recent work has shown that cytotoxic T cells play a central role inimmune-mediated control of cancers-, and monoclonal antibodies thattarget inhibitory receptors on T cells can induce significant clinicalbenefit in patients with advanced disease⁴⁻⁶. However, many of theregulatory mechanisms that result in loss of T cell function withinimmunosuppressive tumors remain unknown. In the following examples, theinventors demonstrate that such regulatory mechanisms can besystematically discovered in vivo in the tumor microenvironment. Theinventors postulated that shRNAs targeting key inhibitors would enablerobust T cell infiltration and accumulation in tumors, despite multipleinhibitory signals. Using a pool shRNA screening approach aimed atidentifying genes that block the function of tumor-infiltrating CD8 Tcells, candidate shRNA were discovered by transfer of shRNA-transduced Tcells into tumor-bearing mice, followed by deep sequencing to quantifythe representation of all hairpins in tumors and lymphoid organs. Themajority of shRNAs induced T cell accumulation in tumors but not thespleen, demonstrating feasibility of discovering shRNAs withdifferential action across tissues. One of the targets was Ppp2r2d, aregulatory subunit of the PP2A phosphatase⁷. Control shRNA-transduced Tcells underwent apoptosis upon recognition of melanoma cells, whilePpp2r2d shRNA-transduced T cells accumulated in tumors due to enhancedproliferation and resistance to apoptosis. Ppp2r2d shRNA-expressing Tcells also significantly delayed tumor growth. This in vivo approach haswide-spread applications to dissect complex immune functions in relevanttissue microenvironments.

Immune cells perform complex surveillance functions throughout the bodyand interact with many different types of cells in distinct tissuemicroenvironments. Therapeutic targets for modulating immune responsesare typically identified in vitro and tested in animal models at a latestage of the process. Here the inventors have addressed the challenge ofhow targets for immune modulation can be systematically discovered invivo. This is a central issue in oncology because strong infiltration byCD8 T cells—which have cytotoxic function against tumor cells—isassociated with a favorable prognosis in multiple types of humancancer^(1,3,8). Unfortunately, this natural defense mechanism isseverely blunted in the majority of patients by multiple inhibitorysignals emanating from the tumor, its stroma, regulatory T cells andmyeloid cell populations.⁹⁻¹¹

Pooled shRNA libraries have been shown to be powerful discoverytools¹²⁻¹⁴. The inventors reasoned that shRNAs capable of restoring CD8T cell function can be systematically discovered in vivo by takingadvantage of the extensive proliferative capacity of T cells followingtriggering of the T cell receptor by a tumor-associated antigen. Whenintroduced into T cells, only a small subset of shRNAs from a pool willrestore T cell proliferation resulting in their enrichment withintumors. Over-representation of active shRNAs within each pool can bequantified by deep sequencing of the shRNA cassette from tumors andsecondary lymphoid organs (FIG. 1).

Experimental animals. C57BL/6 mice, TRP-1 mice (transgenic miceexpressing T-cell receptor (TCR) specific for tyrosinase-related protein1)²³, pmel-1 mice (transgenic mice expressing TCR specific for gp100)¹⁸,and h2m−/− mice²⁴ were purchased from The Jackson Laboratory. TheRag1−/− OT-I mice¹⁶ were purchased from Taconic Farms, Inc. Mice werebred at the Dana-Farber Cancer Institute animal facility. Allexperimental procedures were approved by the Dana-Farber CancerInstitute Animal Care and Use Committee.Cell lines. B16 melanomas, an aggressive tumor that is difficult totreat, express the surrogate tumor antigen Ovalbumin (Ova), which isrecognized by CD8 T cells from OT-I T cell receptor transgenicmice^(16,17). EL4 thymoma³⁸ and B16-F10 melanoma¹⁵ cells were maintainedin RPMI 1640 supplemented with 10% FBS, 2 mM L-glutamine, 100 μg/mlstreptomycin and 100 μg/ml penicillin. Ovabumin-expressing B16 tumorcells (16-Ova) were maintained in the same media with addition of 600μg/mL G418 (Invitrogen).Vectors and shRKA Sequences. shRNAs were selected for 255 genesover-expressed in dysfunctional T cells (anergic or exhausted state).pLKO.3G vector was obtained from The RNAi Consortium. pLKO-Thy1.1,pLKO-Ametrine, pLKO-RFP, pLKO-TFP vectors were modified from pLKO.3Gvector by replacing GFP with the corresponding reporter gene. MurinePpp2r2d and Cblb sequences targeted by 10 selected shRNAs are providedin Table 3 (listed in order of shRNA activity (highest to lowest)). TheLacZ target sequence targeted by a control shRNA is also listed. Allother target sequences can be found in Table 2.

TABLE 3 Murine shRNA # Gene Clone ID Target Sequence LacZ TRCN0000072227GCGCTAATCACGACGCGCTGT (SEQ ID NO: 621) 1 Ppp2r2d TRCN0000080900CCCACATCAGTGCAATGTATT (SEQ ID NO: 386) 2 Ppp2r2d ND000492CCACAGTGGTCGATACATGAT (SEQ ID NO: 385) 3 Ppp2r2d TRCN0000431278GAGAATTAACCTATGGCATTT (SEQ ID NO: 384) 4 Ppp2r2d ND000486GCTCAATAAAGGCCATTACTC (SEQ ID NO: 383) 5 Ppp2r2d TRCN0000080901CCATTTAGAATTACGGCACTA (SEQ ID NO: 380) 6 Ppp2r2d TRCN0000430828ATAGTGATCATGAAACATATC (SEQ ID NO: 375) 7 Ppp2r2d TRCN0000080899GCCACCAATAACTTGTATATA (SEQ ID NO: :374) 8 Ppp2r2d TRCN0000080902CGGTTCAGACAGTGCCATTAT (SEQ ID NO: 381) 9 Ppp2r2d TRCN0000427220TCATCTCCACCGTTGAGTTTA (SEQ II) NO: 378) 10 Ppp2r2d TRCN0000425449ATGCTCATACATATCACATAA (SEQ ID NO: 377) 1 Cblb ND000025CGAGCGATCCGGCTCTTTAAA (SEQ ID NO: 72) 2 Cblb ND000030AGCCAGGTCCAATTCCATTTC (SEQ ID NO: 71) 3 Cblb TRCN0000244606CCCTGATTTAACCGGATTATG (SEQ ID NO: 70) 4 Cblb ND000026ATCGAACATCCCAGATTTAGG (SEQ ID NO: 61) 5 Cblb TRCN0000244603CTACACCTCACGATCATATAA (SEQ ID NO: 59) 6 Cblb ND000024TACACCTCACGATCATATAAA (SEQ ID NO: 67) 7 Cblb TRCN0000244605TGAGCGAGAATGAGTACTTTA (SEQ. ID NO: 60) 8 Cblb TRCN0000244604CCAGATTTAGGCATCTATTTG (SEQ ID NO: 65) 9 Cblb TRCN0000244607CTTGTACTCCAGTACCATAAT (SEQ ID NO: 63) 10 Cblb ND000027TCTACATCGATAGTCTCATGA (SEQ ID NO: 58)Antibodies and flow cytometry. Single-cell suspensions were stained inPBS, 2% FBS with labeled antibodies at 4° C. for 20 minutes, followed bytwo washes with ice-cold PBS, 2% FBS. Cells were analyzed/sorted using aFACSAria (BD Biosciences) and FlowJo software (TriStar). Antibodies usedwere specific for CD4, CD8, Vα2, Vβ5.1/5.2, Thy1.1, CD25, CD44, CD62L,CD69, CD122, CD127, IFNγ, TNFα (BioLegend), PD-1, TIM-3, LAG-3, granzymeB, and H-2Kb (BioLegend), Vα3.2 (eBioscience), Vβ13, Vβ14 (BDBiosciences), phospho-Akt (Ser473) and phospho-Bad (Ser112) (CellSignaling). Apoptotic cells were detected by labeling with annexin V(BioLegend) or activated caspase-3 antibody (Cell Signaling). Mouseanti-CD3/CD28 beads were purchased from Invitrogen.T cell isolation from tumors. B16-Ova melanomas were cut into smallpieces in petri dishes containing 5 mL of PBS, 2% FBS and washed withPBS. Tumors were resuspended in 15 mL RPMI supplemented with 2% FBS, 50U/mL Collagenase Type IV (Invitrogen), 20U/mL DNase (Roche), samplesincubated at 37° C. for 2 hours and tissue further dissociated using agentleMACS Dissociator (Miltenyi Biotech). Suspensions were washed threetimes with PBS and passed through a 70 μM strainer. Lymphocytes wereisolated by density gradient centrifugation and then either analyzed orsorted by flow cytometry using a FACSAria (BD Biosciences).T cell apoptosis. Cytokine pre-treated OT-I cells were transduced withLacZ or Ppp2r2d shRNAs and injected into mice bearing day 14 B16-Ovatumors. After 7 days, intracellular staining was performed using anactivated caspase-3 antibody (Cell Signaling) and CD8/Thy1.1double-positive T cells were gated in the FACS analysis.Immunofluorescence and immunohistochemistry. B16-Ova tumors from micetreated with OT-I T cells expressing LacZ or Ppp2r2d shRNAs(GFP-expressing vector) were cryopreserved in optimal cuttingtemperature (O.C.T.) compound (Tissue-Tek). 10 μm-sections fromcryopreserved tumors were were permeabilized with 0.2% Triton X-100,fixed in 4% paraformaldehyde and stained with a GFP antibody (MolecularProbes) in combination with DAPI. For TUNEL detection, sections werestained with TACS 2 TdT Blue Label (Trevigen) based on manufacturer'sdirections. Samples were visualized using a laser-scanning confocalmicroscope (Leica SP5X) and analyzed with ImageJ software (NIH).qRT-PCR assay. Total RNA was extracted using TRIzol reagent(Invitrogen). RNA was reverse transcribed with the High Capacity cDNAReverse Transcription kit (Applied Biosystems). Real time quantitativePCR reactions were performed as triplicates using an ABI 7900HTinstrument with SYBR green (ABI). Rpl23 levels were used fornormalization. The following primers were used. Ppp2r2d forwardGGAAGCCGACATCATCTCCAC (SEQ ID NO: 622), Ppp2r2d reverseGTGAGCGCGGCCTTTATTCT (SEQ ID NO: 623); Cblb forwardGGTCGCATTTTGGGGATTATTGA (SEQ ID NO: 624), Cblb reverseTTTGGCACAGTCTTACCACTTT (SEQ ID NO: 625); Rpl23 forwardCTGTGAAGGGAATCAAGGGA (SEQ ID NO: 626) and Rpl23 reverseTGTCGAATTACCACTGCTGG (SEQ ID NO: 627).Microarray Analysis. IL-7/IL-15 cultured OT-I T cells were transducedwith one of five experimental shRNAs (Ppp2r2d, Arhgap5, Alk, Egr2,Ptpn2) or a LacZ control shRNA. Infected cells were sorted to purityusing GFP encoded by the vector as a reporter. T cells (5×10⁶) wereinjected i.v. into mice bearing day 14 B16-Ova tumors. Seven days later,shRNA-expressing OT-I T cells (CD8+GFP+) were isolated from tumors andspleens. Cells were sorted twice to high purity and total RNA wasextracted using TRIzol reagent (Invitrogen) for Affymetrix geneexpression profiling (Mouse Genome 430 2.0 Arrays). Arrays for eachshRNA were done in triplicate (6 mice per group).

Nanowell Analysis of Cytokine Production at a Single Cell Level

Materials. Antibodies used for T cell activation were anti-mouse CD3 andanti-mouse CD28 (Biolegend). Antibodies used to capture secretedcytokines were anti-mouse IFNγ (Biolegend), anti-mouse IL-2 (Biolegend),anti-mouse TNFα (Biolegend) and anti-mouse GM-CSF (Biolegend). Detectionantibodies were anti-mouse IFNγ (Biolegend), anti-mouse IL-2(Biolegend), anti-mouse TNFα (Biolegend) and anti-mouse GM-CSF(Biolegend), and they were fluorescently labeled with appropriate AlexaFluor dyes (Invitrogen) following manufacturer's instructions. Thelipids used to prepare supported bilayers were:1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) and1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-(cap biotinyl) (BiotinylCap PE) (Avanti Polar Lipids).

Fabrication of PDMS arrays of nanowells and preparation of supportedlipid bilayers. The array of nanowells was manufactured by injectingpolydimethylsiloxane (PDMS, Dow Corning) prepared at a 10:1base/catalyst weight ratio into a custom-built mold encasing amicropatterned silicon master. Arrays of nanowells were cured at 70° C.for 4-16 h. Each array comprised 72×24 blocks, each containing a 7×7 (50μm×50 μm×50 μm) subarray of nanowells (total of 84,672 wells). The PDMSarrays adhered directly to a 3″×1″ glass slide forming a 1 mm thicklayer. Supported lipid bilayers were prepared as described previously14.Bilayers were generated by applying DOPC liposomes containing 2 mol %biotin-Cap-PE lipids on the PDMS array of nanowells. The surfaces wererinsed with deionized water to remove excess liposomes. Before use, thelipid bilayer was blocked with BSA in PBS (100 μg/mL) for 45 minutes.The bilayer was then incubated with 1 μg/mL of streptavidin in asolution of 100 μg/mL BSA in PBS, followed by incubation withbiotinylated CD3 and CD28 antibodies. The device was rinsed extensivelywith PBS before adding the cells.

Microengraving. Capture antibodies were diluted in borate buffer (50 mMsodium borate, 8 mM sucrose, and 50 mM NaCl, pH 9.0) to a finalconcentration of 10 μg/mL and deposited on the surface of epoxy-modifiedslides for 1 h at room temperature. Slides were blocked with 3% non-fatmilk in PBST (PBS with 0.05% (v/v) Tween 20) for 30 min at roomtemperature and washed with PBS before placing them into contact withthe PDMS array of nanowells. A suspension of T cells was dispensed ontothe surface of the nanowells, modified with a supported lipid bilayer inmedia and allowed to settle into the wells. The density of suspendedcells applied to the array was optimized empirically to maximize welloccupancy by single cells (typically 30% of wells). After incubation ofthe cell-loaded wells, a glass slide coated with capture antibodies wasthen placed onto the loaded array for cytokine capture. The microarrayand glass slide were held together by compression in a hybridizationchamber (Agilent Technologies, G2534A) and incubated for 1h at 37° C.with 5% CO₂. The glass slide was then separated from the array andplaced in PBS. After microengraving, slides were incubated for 30 minwith blocking buffer (PBS, 10 mg/mL BSA, 0.05% (v/v) Tween-20, 2% mouseserum and 2 mM sodium azide), washed with PBST (PBS+0.05% v/v Tween-20),and then incubated with fluorescence detection antibodies at 1 μg/mL for45 min at 25° C. The slides were washed with PBST and PBS, rinsedbriefly with water, and dried with a N₂ stream. Reference slides weregenerated at the end of each experiment with the same detectionantibodies used on the printed slides. For reference slides, antibodieswere diluted in water, spotted onto blank poly-L-lysine slides (1μL/spot), and the reference slides were dried under vacuum. Slides werescanned using a Genepix 4200AL microarray scanner (Molecular Devices).The median fluorescence intensity of each spot was extracted usingGenepix Pro.

On-chip image-based cytometry. Before imaging, T cells were stained withCellMask™ Plasma Membrane Stain (Invitrogen, Life Technologies) andSYTOX green (for detection of dead cells, Life Technologies). Thecell-loaded arrays of nanowells were mounted face-up on the microscopewith a coverslip placed on top of the array. Images were acquired on anautomated inverted epifluorescence microscope (Carl Zeiss). Transmittedlight and epifluoresence micrographs were collected block-by-block (7×7microwells per block). The resulting collection of images was analyzedusing a custom program to determine the number of cells present in eachwell and the mean fluorescence intensity of each label. Only viable Tcells were considered for the analysis. Although the cells expressedGFP, the fluorescence intensity of GFP was negligible under the utilizedmicroscope acquisition setting compared to SYTOX green, enablingidentification of dead cells.

Data analysis. Data extracted from both on-chip cytometry and printedcytokines were matched in Microsoft Excel using unique identifiersassigned to each well within the array. The dataset was filtered toinclude wells containing only single cells. To compensate from signalbleed-through and convert the measured fluorescence intensity for thecaptured cytokines from a given cell into a rate of secretion, the datafrom standard calibration curves (from reference slides) prepared withknown amounts of detection antibodies was used to convert measuredintensities to a number of molecules, as described previously (Han, Q.,et. al., Multidimensional analysis of the frequencies and rates ofcytokine secretion from single cells by quantitative microengraving. LabChip 10, 1391-1400, doi:10.1039/b926849a (2010).

Example 1: In Vivo RNAi Discovery of Immunotherapy Targets

Two large primary screens were performed, with the first focusing ongenes over-expressed in dysfunctional T cells (T cell anergy orexhaustion; 255 genes, 1,275 shRNAs divided into two pools), and thesecond on kinases/phosphatases (1,307 genes, 6,535 shRNAs divided intoseven pools) (Table 4). In these primary screens, each gene wasrepresented by ˜5 shRNAs.

TABLE 4 T cell Kinase/ shRNA Dysfunction Phosphatase Enrichment 1^(st)Genes 255 1307 4-10×: 123 Screen shRNAs 1275 6535 10-20×: 17 Candidate32 82 >20×: 1 Genes 2^(nd) Genes 32 43 4-10×: 191 Screen shRNAs 480 64510-20×: 27 Candidate 17 26 >20×: 1 GenesshRNAs targeting 255 genes over-expressed in dysfunctional T cells(anergic or exhausted state)³⁷ and 1,307 kinase/phosphatase genes (˜5shRNAs per gene) were obtained from The RNAi Consortium (TRC; BroadInstitute, Cambridge, Mass., USA). Nine pools were created and shRNAssubcloned into the pLKO-Thy1.1 lentiviral vector. Each pool alsocontained 85 negative-control shRNAs (number of shRNAs: GFP, 24; LacZ,20; luciferase 25; RFP 16). OT-I T cells isolated by negative selection(Stemcell Technologies) were cultured with IL-7 (5 ng/mL, Peprotech) andIL-15 (100 ng/mL, Peprotech) in complete RPMI media (RPM 11640, 10% FBS,20 mM HEPES, 1 mM sodium pyruvate, 0.05 mM 2-mercaptoethonal, 2 mML-glutamine, 100 μg/ml streptomycin and 100 μg/ml penicillin). On day 2,OT-I T cells were spin-infected with lentiviral pools (nine lentiviralshRNA pools and a LacZ control shRNA lentiviral vector control)supplemented with protamine sulfate (5 μg/mL) in 24-well plates coatedwith retronectin (5 μg/mL) at a multiplicity of infection (MOI) of 15.Typically, 5×10⁶ OT-1 T cells were infected for each pool.

Following infection, OT-I cells were cultured with IL-7 (2.5 ng/mL),IL-15 (50 ng/mL) and IL-2 (2 ng/mL) in complete RPMI media. On day 5,live shRNA-transduced T were enriched using a dead cell removal kit(Miltenyi), and infected cells were positively selected based on Thy1.1marker (Stemcell Technologies) to 50-60% Thy1.1 positivity. Successfultransduction was monitored by surface expression of the Thy1.1 reporter(FIG. 2). T cells (5×10⁶) were injected i.v. into C57BL/6 mice bearingday 14 B16-Ova tumors (15 mice per shRNA pool)(number of animals chosento provide sufficient cells for T cell isolation and PCR). Genomic DNAwas isolated from 5×10⁶ enriched OT-I cells as the start population fordeep sequencing. Seven days later, shRNA-expressing T cells(CD8⁺Vα2⁺Vβ5⁺Thy1.1⁺) were isolated by flow cytometry from tumors,spleens, tumor-draining lymph nodes and irrelevant lymph nodes forisolation of genomic DNA, followed by PCR amplification of the shRNAcassette. (FIG. 3) Genomic DNA was isolated (Qiagen) and deep-sequencingtemplates were generated by PCR of the shRNA cassette. Representation ofshRNAs in each pool was analyzed by deep sequencing using an IlluminaGenome Analyzer³⁰. Data were normalized using the average reads ofcontrol shRNAs in each pool. Kinase/phosphatase genes were selected forthe secondary screen based on expression levels in T cells.

For certain genes, shRNAs were over-represented in all tested tissuescompared to the starting T cell population (e.g. SHP-1), indicative ofenhanced proliferation independent of TCR recognition of a tumorantigen. For other genes, there was a selective loss of shRNAs withintumors (e.g. ZAP-70, a critical kinase in the T cell activationpathway). We focused our analysis on genes whose shRNAs showedsubstantial over-representation in tumor but not spleen, a secondarylymphoid organ. Substantial T cell accumulation in tumors was observedfor a number of shRNAs, despite the immunosuppressive environment. Forsecondary screens, we created focused pools in which each candidate genewas represented by ˜15 shRNAs.

Primary data from this analysis are shown for three genes in FIG. 4:LacZ (negative control), Cblb (an E3 ubiquitin ligase that induces Tcell receptor internalization)¹⁹ and Ppp2r2d (not previously studied inT cells). For both Ppp2r2d and Cblb, five shRNAs were substantiallyincreased in tumors (red) compared to spleen, while no enrichment wasobserved for LacZ shRNAs. Overall, 43 genes met the following criteria:≥4-fold enrichment for 3 or more shRNAs in tumors compared to spleen(Table 5, FIG. 4, FIG. 5). The set included gene products previouslyidentified as inhibitors of T cell receptor signaling (including Cblb,Dgka, Dgkz, Ptpn2) as well as other well-known inhibitors of T cellfunction (e.g. Smad2, Socs1, Socs3, Egr2), validating our approach(Table 5, Table 6).²⁰⁻²² Table 5 describes the functional classificationof candidate genes from the secondary screen.

TABLE 5 Function Genes Inhibition of TCR signaling Cbib, Dgka, Dgkz,Fyn, Inpp5b, Ppp3cc, Ptpn2, Stk17b, Tnk1 Phosphoinositol metabolismDgka, Dgkz, Impk, Inpp5b, Sbf1 Inhibitory cytokine signaling Smad2,Socs1, Socs 3 pathways AMP signaling, inhibition of Entpd1, Prkab2, NuakmTOR Cell cycle Cdkn2a, Pkd1, Ppp2r2d Actin and microtubules Arhgap5,Mast2, Rock 1 Potential nuclear functions Blvrb, Egr2, Impk, Jun, Ppm1gRole in cancel cells Alk, Arhgap5, Eif2ak3, Hipk1, Met, Nuak, Pdzklip,Rock1, Yes1

Secondary screens were performed focusing on genes whose shRNAs showedsubstantial over-representation in tumor but not spleen, a secondarylymphoid organ. Substantial T cell accumulation in tumors was observedfor a number of shRNAs, despite the immunosuppressive environment. Forthese secondary screens, ˜10 additional shRNAs were synthesized for eachgene (IDT) for a total of ˜15 shRNAs per gene. These focused poolscontained 85 negative-control shRNAs. Two control shRNAs (one for RFP,one for luciferase) showed some enrichment in tumors relative to spleen(4.0 and 5.1-fold, respectively). Cut-off in the secondary screen wasdefined as ≥3 shRNAs with ≥4 fold enrichment in tumor relative tospleen. Screening results were validated at a cellular level byintroducing individual shRNAs into T cells, along with a reporterprotein (GFP, TFP, RFP or Ametrine fluorescent proteins, Thy1.1). Thisapproach enabled simultaneous testing of five shRNAs in an animal (threemice per group). Proliferation of shRNA-transduced T cells wasvisualized based on CFSE dilution after 24 hours as well as 3, 5 and 7days. In addition, intracellular staining was performed on days 3, 5 and7 for IFNγ, TNF and isotype controls. Results from the primary andsecondary screen of T cell dysfunction pool shRNA library are providedin Table 6. Genes for which at least 3 shRNAs showed >4 fold enrichmentin tumors are listed, along with a brief description of their function.Results from secondary screen of kinase and phosphatase shRNA librariesare shown in Table 7.

TABLE 6 Total # Enrichment Symbol shRNAs (fold) Function Dgkz 6 5.2-14.0Phosphorylates and thereby inactivates DAG Egr2 6 4.0-10.2 Transcriptionfactor involved in T cell unresponsiveness, expression of Cblb Smad2 56.7-30.3 TGF beta signaling pathway Cblb 5 4.1-10.8 E3 ubiquitin ligase(degradation of TCR and signaling molecules; ko mice reject tumors)Inpp5b 5 4.3-9.5 Inositol polyphosphate-5-phosphatase, hydrolyzes PIP2Socs1 5 4.1-8.5 Inhibitor of cytokine signaling Jun 5 5.2-6.4 PersistentAP-1 activation in tumor-infiltrating T cells leads to upregulated PD-1Entpd1 4 6.5-13.3 Extracellular degradation of ATP to AMP (an inhibitorysignal through AMP kinase) Vamp7 4 4.0-11.3 Vesicle associatedtransmembrane protein Dgka 4 5.0-10.2 Phosphorylates and therebyinactivates DAG Mdfic 4 4.4-10.0 Inhibits viral gene expression,interacts with cyclin T1 and T2 Nptxr 4 4.0-7.2 Pentraxin Receptor F11r4 4.6-6.8 Cell migration Socs3 4 4.6-6.3 Inhibitor of cytokine signalingPdzklip1 3 4.8-12.9 Pdzk1 interacting protein, expression correlateswith tumor progression Fyn 3 4.1-6.5 inhibits activation of resting Tcells (through Csk) Ypel2 3 4.6-5.1 Function unknown

TABLE 7 Total # Enrichment Symbol shRNAs (fold) Function Rbks 6 4.0-12.8 Ribokinase carbohydrate metabolism Pkd1 6 4.9-9.9 Cell cyclearrest (activates JAK/STAT pathway) Ppp2r2d 5  4.0-17.2 Regulatorysubunit of PP2A phosphatase Eif2ak3 5  4.8-13.4 ER stress sensor,resistance of cancer cells to chemotherapy Ptpn2 5 4.7-7.4 Inhibitor ofT cell and cytokine signaling Hipk1 4  4.5-12.3 Interacts with p53 andc-myb, knockout mice develop fewer carcinogen-induced tumors Grk6 44.2-11  Regulator of particular G-protein coupled receptors Cdkn2a 44.1-7.2 G1 cell cycle arrest and apoptosis in T cells Sbf1 4 4.8-6.9Activates MTMR2, which dephosphorylates PI(3)P and PI(3,5)P2 Ipmk 44.0-6.9 Inositol polyphosphate kinase, nuclear functions such aschromatin remodeling Rock1 4 44.1-6.5  Rho kinase, inhibitors have shownactivity in mouse models of cancer Stk17b 4 4.0-6.4 Inhibitor of T cellsignaling forms complex with protein kinase D Mast2 4 4.1-5.1Microtubule-associated serine/threonine kinase Arhgap5 3  6.0-15.7Negative regulator of Rho GTPases, inhibition can reduce cancer cellinvasion Alk 3  9.6-13.5 Anaplastic lymphoma kinase (translocation ofnucleophosmin and ALK in ALCL) Nuak 3  4.5-13.1 Member of AMP-activatedprotein kinase-related kinase family, oncogene in melanoma Akap8I 3 4.4-11.8 A-kinase anchoring protein, recruits cAMP-deperident proteinkinase (PKA) to chromatin Pdp1 3 4.1-9.8 Pyruvate dehydrogenasephosphatase 1, regulation of glucose metabolism Yes1 3 5.4-9.7 Srcfamily kinase, oncogene in several tumors Met 3 4.1-8.9 Receptortyrosine kinase, involved in hepatocellular and other cancers Ppm1g 36.2-8.2 Dephosphorylates spliceosome substrates and histories H2A-H2BBlvrb 3 5.3-8.0 Biliverdin reductase, also transcription factor, arrestof cell cycle Tnk1 3 5.2-7.6 Downregulates Ras pathway (phosphorylationof Grb2), inhibition of NF-kB pathway Prkab2 3 4.1-7.0 Subunit of AMPkinase, inhibits fatty acid synthesis and mTOR pathway Trpm7 3 4.9-5.9Ion channel and serine-threonine kinase Ppp3cc 3 4.2-4.4 Regulatorysubunit of calcincurin (phosphatase in T cell receptor signaling)

Example 2: shRNA-Driven Expansion of CD4 and CD8 T Cells in B16Melanomas

Positive shRNAs from deep sequencing analysis were cloned intolentiviral vectors encoding five different reporter proteins (GFP, TFP,RFP or Ametine fluorescent proteins, Thy1.1). Cytokine-pretreated OT-1ITcells were transduced with lentiviral vectors driving expression of asingle shRNA and a reporter protein; 1×10⁶ T cells of each populationwere mixed and co-injected i.v. into C57BL/6 mice bearing day 14 B16-Ovatumors. After seven days T cells were isolated from tumors, spleens andlymph nodes, and the percentage of reporter-positive CD8′Vα2⁺Vβ5⁺ Tcells was determined by flow cytometry based on co-introduced reporters.Fold-enrichment in tumors compared to spleen was calculated based on thepercentage of OT-I T cells in each organ expressing a particularreporter. When the control LacZ shRNA was expressed in CD8 OT-I T cells,the frequency of shRNA-expressing CD8 OT-I T cells was lower in tumorscompared to spleen (˜2-fold). In contrast, experimental shRNAs inducedaccumulation of CD8 OT-I T cells in tumors but not the spleen (FIG. 6,FIG. 7). For seven of these shRNAs (e.g., Ppp2r2D, Eif2ak3, Arhgap5,Smad2, Akap8I, Rbks and Egr2), T cell accumulation in tumorswas >10-fold relative to spleen. The strongest phenotype was observedwith shRNAs targeting Ppp2r2d, a regulatory subunit of the PP2Aphosphatase7.

CD8⁺OT-I or CD4⁺ TRP-1 T cells expressing Ppp2r2d or LacZ shRNAs wereinjected into mice bearing day 14 B16-Ova tumors. shRNA-expressing Tcells were identified in tumors and spleens using Thy1.1 reporter (FIG.8a , % Thy1.1⁺ CD8 T cells, left panels). Total numbers of LacZ orPpp2r2d shRNA-expressing T cells were determined in tumors and spleens 7days following transfer of 2×10⁶ shRNA-expressing cells (FIG. 8a , rightpanels). Fold-enrichment of Ppp2r2d versus LacZ shRNA-expressing T cellsin tumors is indicated. Ppp2r2d shRNA not only induced accumulation ofOT-I CD8 T cells, but also CD4 T cells (from TRP-1 TCR transgenic mice),with T cell numbers in tumors being significantly higher when Ppp2r2drather than LacZ shRNA was expressed (36.3-fold for CD8; 16.2-fold forCD4 T cells) (FIGS. 8a-8b ).

T cell enrichment in tumors compared to spleen for cells expressing apanel of Ppp2r2d or Cblb shRNAs (FIG. 17, upper panels) Ppp2r2d and CbbmRNA levels were also measured by qPCR prior to T cell transfer (FIG.17, lower panels). The strongest T cell enrichment in tumors wasobserved for shRNAs with >80% knock-down efficiency at the mRNA level(shRNAs #1 and 2 for both Ppp2r2d and Cblb). CD8 T cell accumulationcorrelated with the degree of Ppp2r2d knock-down, and two Ppp2r2d shRNAswith the highest in vivo activity induced the lowest levels of Ppp2r2dmRNA (FIG. 17).

Ppp2r2d knockdown was also confirmed at the protein level using aquantitative mass spectrometry approach (FIG. 18). A previously reportedapproach for absolute quantification (AQUA) of proteins from celllysates by mass spectrometry was used to measure the effect of Ppp2r2dshRNA expression at the protein level (Gerber, S. A., Rush, J., Stemman,O., Kirschner, M. W. & Gygi, S. P. Absolute quantification of proteinsand phosphoproteins from cell lysates by tandem MS. PNAS, 100, 6940-6945(2003). This strategy is based on a ‘selective reaction monitoring’approach in which a synthetic peptide with incorporated stable isotopesis used as an internal standard for mass spectrometry analysis. OT-Icells expressing LacZ or Ppp2r2d shRNAs were sorted to purity usingFACS. Cells (1×10⁶) were lysed in 1 ml of MPER extraction reagent(Pierce) containing a Protease Inhibitor Cocktail (Sigma), 1 mM EDTA and1 mM PMSF for 15 minutes on ice with occasional vortexing. Cell debriswas removed by centrifugation and the protein supernatant was filtered(0.2 μm SpinX centrifuge filter, Costar). Protein concentration wasdetermined by Bradford assay (Biorad) and UV280 nm analysis (Nanodropinstrument); 0.1 mg of cellular protein was separated by SDS-PAGE andstained with Coomassie blue reagent (Pierce). Gel bands corresponding toa MW range of 45-60 kDa were excised followed by in-gel digestion ofproteins with trypsin. Eluted peptides were spiked with 300 fmol ofisotopically labeled Ppp2r2d (FFEEPEDPSS[13C-15N-R]—OH)(SEQ ID NO: 628)and Actin B (GYSFTTTAE[13C-15N-R]—OH) (SEQ ID NO: 629) peptides (21stCentury Biochemicals) for quantification by LC MS/MS (LTQ XL Orbitrap,Thermo Scientific). The Ppp2r2d peptide was chosen from a region of theprotein that differs from other regulatory subunits of PP2A. Initially,a LC-MS/MS run of a LacZ shRNA sample was analyzed to localize thePpp2r2d and Actin B peptides that were being monitored. The absolutequantification AQUA peptides co-eluted with the corresponding endogenouspeptides from the reverse-phase column, yet their higher MW (10 Da)enabled the ratio of peak intensity for endogenous and AQUA peptides tobe determined using abundant peptide fragment ions. Triplicate sampleswere analyzed by SDS-PAGE-LC-MS/MS and statistical significance wasdetermined using Graphpad Prism 6.0 software using a two-sided Studentt-test (F test, * p=0.0062).

The specificity of Ppp2r2d shRNA was determined. Ppp2r2d shRNA activitywas specific because the phenotype was reversed when a mutated Ppp2r2dcDNA (with wild-type protein sequence, but mutated DNA sequence at theshRNA binding site) was co-introduced with the Ppp2r2d shRNA (FIG. 9, 10a-c). Furthermore, OT-1 CD8 T cells over-expressed Ppp2r2d in tumorscompared to spleen (in the absence of any shRNA expression), suggestingthat it is an intrinsic component of the signaling network inhibiting Tcell function in tumors (FIG. 19).

OT-1 T cells transduced with lentiviral vectors driving expression ofLacZ shRNA, Ppp2r2d shRNA, Ppp2r2d shRNA. Mutant Ppp2r2d cDNA withpreserved protein sequence but disrupted shRNA binding site weregenerated. Wild-type Ppp2r2d cDNA was isolated by RT-PCR using forwardprimer GGATCCATGGCAGGAGCTGGAGGC (SEQ ID NO: 630) and reverse primer:GCTAGCATTAATTTTGTCCTGGAATATATACAAGTTATTGGTGG (SEQ ID NO: 631). Thetarget sequence of Ppp2r2d shRNA, CCCACATCAGTGCAATGTATT (SEQ ID NO: 632)was mutated to TCCCCACCAATGTAACGTGTT (SEQ ID NO: 633) by overlapping PCR(which conserves protein coding sequence) using forward primer:TCCATCCCCACCAATGTAACGTGTTTGTTTACAGCAGCAGCAAGG (SEQ ID NO: 634) andreverse primer: AAACAAACACGTTACATTGGTGGGGATGGAACTCTGCGGCAGTGA (SEQ IDNO: 635). (FIG. 10a ) Both wild-type and mutant Ppp2r2d cDNAs werecloned into a modified pLKO.3 vector with a 2A ribosomal skippeptide-GFP sequence (resulting in stoichiometric Ppp2r2d and GFPexpression in cells). Constructs were introduced into EL4 thymoma cells.GFP-expressing EL4 cells were sorted to purity and then transduced withLacZ or Ppp2r2d shRNA lentiviral vectors driving expression of a Thy1.1reporter. shRNA-transduced (Thy1.1⁺) cells were analyzed by flowcytometry for GFP expression. The Ppp2r2d shRNA reduced GFP levels whenwild-type Ppp2r2d. The Ppp2r2d shRNA was not able to reduce expressionof the GFP reporter in cells expressing the mutant Ppp2r2d cDNA,demonstrating that the shRNA binding site had been successfully mutated.(FIG. 10a )

Expression of Ppp2r2d mutant cDNA also prevents phenotype induced byPpp2r2d shRNA. (FIG. 10b ) Ppp2r2d shRNA was cloned into the mutantPpp2r2d cDNA-2A-GFP construct which resulted in co-expression of Ppp2r2dshRNA and mutated Ppp2r2d cDNA in one vector. OT-I T cells wereseparately infected with lentiviruses encoding LacZ shRNA (Thy1.1),Ppp2r2d shRNA (Ametrine) or Ppp2r2d shRNA plus mutant Ppp2r2d cDNA(GFP). (FIG. 10b ) These three populations there then mixed at the sameratio and injected into mice bearing day 14 B16-Ova tumors. On day 7,each T cell population was quantified in tumors and spleens by gating onOT-I (CD8 Vα2⁺Vβ5)-T cells followed by analysis of populations marked byThy1.1, Ametrine or GFP expression. The percentage of each T cellpopulation in tumors and spleens was quantified by gating on Vα2⁺Vβ5⁺ Tcells; transduced cells were detected based on expression of Thy1.1 orAmetrine/GFP fluorescent reporters and the results are shown in FIG. 10b. (representative data from 2 independent experiments, n=3 mice perexperiment).

FIG. 10c provides real-time PCR analysis for Ppp2r2d expression in OT-IT cells transduced with LacZ shRNA, Ppp2r2d shRNA, and Ppp2r2d shRNAplus Ppp2r2d mutant cDNA. Also, the Ppp2r2d shRNA with the highest invivo activity was associated with the lowest levels of Ppp2r2d mRNA(FIG. 11).

Microarray analysis of tumor-infiltrating T cells expressingexperimental or control shRNAs showed that each shRNA induced a distinctset of gene expression changes, with some overlap between particularshRNAs (FIG. 12a-c ). Two genes (Egr2 and Ptpn2) have known functions inT cells. Enrichment in tumor versus spleen was calculated based on deepsequencing results from the secondary screen. (FIG. 12a ) Clustering ofmean expression levels for mRNAs found to be significantly regulated byT cells in spleens or tumors expressing the LacZ control shRNA or one offive experimental shRNAs. (FIG. 12b ) Significant expression differenceswere defined as an Anova p value<0.01 between T cells expressing LacZcontrol shRNA or one of five experimental shRNAs (Alk, Arhgap5, Egr2,Ptpn2 or Ppp2r2d) (JMP-Genomics 6.0, SAS Institute Inc.). mRNAssignificantly regulated in one or more treatment groups are shown afterclustering (Fast Ward). FIG. 12c is a Venn diagram showing overlapsbetween expression signatures by tumor-infiltrating T cells transducedwith one of the five experimental shRNAs (signatures defined as an Anovap<0.01 as described above). Indicated are the numbers of overlappingprobe IDs for any combination of the 5 signatures, as indicated by theoverlapping ovals. The significance of the overlaps versus that expectedby random chance (Fishers Exact Test) is shown in the accompanyingtable.

Example 3: Changes in T Cell Function Induced by Ppp2r2d

For this example, the cellular mechanisms driving T cell accumulation bya Ppp2r2d shRNA in tumors—specifically T cell infiltration, accumulationand apoptosis were examined. T cell infiltration into tumors wasassessed by transfer of OT-I CD8 T cells labeled with a cytosolic dye,CFSE. OT-I T cells expressing Ppp2r2d or LacZ shRNAs were labeled withCFSE and injected into B16-Ova tumor-bearing mice. Twenty-four hourslater transduced T cells were isolated from tumors and spleens andquantified by flow cytometry. OT-I T cells expressing LacZ or Ppp2r2dshRNAs were purified using the Thy1.1 reporter and cultured in completeRPMI media without added cytokines for 24 hours. Live cells isolated byFicoll density gradient centrifugation (Sigma) were labeled with CFSE(carboxyfluorescein diacetate, succinimidyl ester, Invitrogen), and2×10⁶ labeled cells were injected into mice bearing day 14 B16-Ovatumors. CFSE dilution was quantified by flow cytometry at 24 hours anddays 3, 5 and 7 following transfer. In addition, intracellular stainingwas performed on days 3, 5 and 7 for IFNγ, TNFα and isotype controls(BD). No differences were observed in the frequency of Ppp2r2d or LacZshRNA-transduced CD8 T cells in tumors on day 1, arguing against asubstantial effect on T cell infiltration (FIG. 13a ). However, analysisof later time points (days 3 and 5) demonstrated a higher degree ofproliferation (based on CFSE dilution) by Ppp2r2d compared to LacZshRNA-transduced T cells (FIG. 13b , FIG. 20a ). Ppp2r2dshRNA-transduced T cells also produced higher levels of interferon-γ, acytokine critical for anti-tumor immunity (FIG. 13e ). The action ofPpp2r2d was downstream of T cell receptor activation because T cellaccumulation was enhanced in tumors and to a lesser extent intumor-draining lymph nodes. In contrast, no accumulation was observed inirrelevant lymph nodes or the spleen where the relevant antigen is notpresented to T cells (FIG. 15). A substantial degree of T cellaccumulation was even observed for LacZ shRNA-transduced T cells(complete dilution of CFSE dye by day 7), despite the presence of smallnumbers of such cells in tumors. This suggested that LacZshRNA-transduced T cells were lost by apoptosis. Indeed, a largerpercentage of tumor-infiltrating T cells were labeled with an antibodyspecific for active caspase-3 when the LacZ control shRNA (rather thanPpp2r2d shRNA) was expressed (FIG. 13g , FIG. 20b ). Furthermore,co-culture of CD8 T cells with B16-Ova tumor cells showed that themajority of LacZ shRNA expressing T cells became apoptotic (65.7%) whilemost Ppp2r2d shRNA-transduced T cells were viable (89.5%, FIG. 13c ).

OT-I T cells expressing LacZ or Ppp2r2d shRNAs were purified based onThy1.1 expression and labeled with CFSE, as described above. CFSElabeled OT-I T cells (1-10⁵) were co-cultured with 5×10⁴ B16-Ova cellsper well in a 96-well plate for 72 h. Prior to the assay, B16-Ova cellswere exposed to 1 ng/mL IFNγ for 48 hours (to induce MHC class I, whichis not expressed in vitro) and washed three times. Apoptosis of OT-I Tcells was detected by annexin V labeling of CD8⁺ cells. (FIG. 13c )Intracellular staining of phospho-AKT (Ser473), phopsho-Bad (Ser 112),Bcl-2 and isotype control was performed at 48 hours using a BDintracellular staining kit. Co-culture of CD8 T cells with B16-Ova tumorcells indeed showed that the majority of LacZ shRNA expressing T cellswere apoptotic (65.7%) while the majority of Ppp2r2d shRNA-transduced Tcells were viable (89.5%, FIG. 13c ). A similar phenotype was observedwhen Ppp2r2d and LacZ shRNA-expressing T cells were stimulated withimmobilized CD3 antibody in the absence of CD28 costimulation (FIG. 14).Specifically, B16-Ova cells (2×10⁵) were injected s.c. into femaleC57BL/6 mice (10 weeks of age). On day 12, mice bearing tumors ofsimilar size were divided into 7 groups (7-8 mice/group). Anti-CD3/CD28bead activated CD4 TRP-1 or/and CD8 OT-I T cells infected with Ppp2r2dor LacZ shRNA vectors (2×10⁶ T cells each) were injected i.v. on days 12and day 17. For the treatment of B16 tumors, mice were treated at day 10with anti-CD3/CD28 bead activated CD4 TRP-1 and CD8 pmel-1 T cellsexpressing Ppp2r2d or LacZ shRNAs (3×10⁶ T cells each). Tumor size wasmeasured every three days following transfer and calculated aslength/width. Mice with tumors ≥20 mm on the longest axis weresacrificed.

These results suggested the possibility that Ppp2r2d shRNA-transducedCD8 T cells may be able to proliferate and survive even when theyrecognize their antigen directly presented by B16-Ova tumor cells. Thisidea was tested by implantation of tumor cells into b2m−/− mice whichare deficient in expression of MHC class I proteins²⁴. In such mice,only tumor cells but not professional antigen presenting cells of thehost could present tumor antigens to T cells. Indeed, Ppp2r2dshRNA-transduced OT-I CD8 T cells showed massive accumulation withinB16-Ova tumors in b2m−/− mice (FIG. 12f ) while there were very smallnumbers of T cells in contralateral B16 tumors that lacked expression ofthe Ova antigen. T cells expressing a Ppp2r2d shRNA could thuseffectively proliferate and survive in response to tumor cells, despitea lack of suitable co-stimulatory signals and an inhibitorymicroenvironment.

Ex vivo analysis of tumor-infiltrating T cells at a single-cell levelusing a nanowell device also demonstrated that Ppp2r2d silencingincreased cytokine production by T cells (FIG. 21a-c ). T cells wereactivated for 3 hours by CD3/CD28 antibodies on lipid bilayers, followedby 1 hour cytokine capture on antibody-coated slides. CD8 T cells showeda higher secretion rate for IFNγ, IL-2 and GM-CSF, and a larger fractionof T cells more than one cytokine (FIG. 21b, c ). The presence of largernumbers of IFNγ-producing T cells was confirmed by intracellularcytokine staining (FIG. 21d , FIG. 20).

PP2A phosphatase is composed of a catalytic and scaffolding subunit, andits substrate specificity is determined by one of many regulatorysubunits⁷. Ppp2r2d directs PP2A to Cdk1 substrates during interphase andanaphase; it thereby inhibits entry into mitosis and induces exit frommitosis²⁵. PP2A plays a gatekeeper role for BAD-mediated apoptosis.Phosphorylated BAD is sequestered in its inactive form in the cytosol by14-3-3, while dephosphorylated BAD is targeted to mitochondria where itcauses cell death by binding Bcl-XL and Bcl-2²⁶. PP2A phosphatases havealso been shown to interact with the cytoplasmic domains of CD28 andCTLA-4 as well as Carmal (upstream of the NF-κB pathway), but it is notknown which regulatory subunits are required for these activities;Ppp2r2d antibodies suitable for the required biochemical studies arecurrently not available.

Example 4: Silencing of Ppp2r2d Enhances Anti-Tumor Activity of CD4 andCD8 T cells

The ability of a Ppp2r2d shRNA to enhance the efficacy of adoptive Tcell therapy was assesed. B16-Ova tumor cells (2×10⁵) were injectedsubcutaneously into female C57BL/6 mice (10 weeks of age). On day 12,mice bearing tumors of similar size were divided into seven groups (7-8mice/group), either receiving no T cells, 2×10⁶ shRNA-transduced TRP-1CD4 T cells, 2×10⁶ shRNA infected OT-I CD8 T cells, or both CD4 and CD8T cells (days 12 and day 17). According to group, anti-CD3/CD28 beadactivated CD4 TRP-1 or/and CD8 OT-I T cells infected with Ppp2r2d orLacZ shRNA vectors (2×10⁶ T cells each) were injected i.v. on days 12and day 17. For the treatment of B16 tumors, mice were treated at day 10with anti-CD3/CD28 bead activated CD4 TRP-1 and CD8 pmel-1 T cellsexpressing Ppp2r2d or LacZ shRNAs (3×10⁶ T cells each). Tumor size wasmeasured every three days following transfer and calculated aslength×width. Mice with tumors ≥20 mm on the longest axis weresacrificed. Ppp2r2d-silencing improved the therapeutic activity of CD4and CD8 T cells, and a synergistic effect was observed when Ppp2r2dshRNA-transduced CD4 and CD8 T cells were co-administered (FIG. 16a, b). A Ppp2r2d shRNA also enhanced anti-tumor responses when introducedinto T cells specific for endogenous tumor antigens (pmel-1 CD8 T cellsand TRP-1 CD4 T cells) (FIG. 16c ).

Ppp2r2d-silenced T cells acquired an effector phenotype in tumors (FIG.22a ) and >30% of the cells expressed granzyme B (FIG. 23a ). Consistentwith greatly increased numbers of such effector T cells in tumors (FIG.23b ), TUNEL staining demonstrated increased apoptosis in tumors whenPpp2r2d rather than LacZ shRNA expressing T cells were present (FIG. 23c). B16 melanomas are highly aggressive tumors in part because MHC classI expression is very low. Interestingly, Ppp2r2d but not LacZshRNA-expressing T cells significantly increased MHC class I expression(H-2Kb) by tumor cells (FIG. 23d ), possibly due to the observedincrease in IFNγ secretion by T cells (FIG. 21a-c , FIG. 13e ). APpp2r2d shRNA did not reduce expression of inhibitory PD-1 or LAG-3receptors on tumor-infiltrating T cells, demonstrating that itsmechanism of action is distinct from these known negative regulators ofT cell function (FIG. 22b ). This finding suggests combinationapproaches targeting these intracellular and cell surface molecules.

These results establish the feasibility of in vivo discovery of noveltargets for immunotherapy in complex tissue microenvironments. Theinventors have shown that it is possible to discover genes withdifferential action across tissues, as exemplified by T cellaccumulation in tumors compared to secondary lymphoid organs. For geneswith tissue-selective action, T cell accumulation and survival arelikely to be under the control of the T cell receptor and therefore donot occur in tissues lacking presentation of a relevant antigen. Manyvariations of the approach presented here can be envisioned toinvestigate control of particular immune cell functions in vivo. Forexample, fluorescent reporters for expression of cytokines or cytotoxicmolecules (granzyme B, perforin) could be integrated into our approachto discover genes that control critical T cell effector functions intumors.

Targeting of key regulatory switches may offer new approaches to modifythe activity of T cells in cancer and other pathologies. The efficacy ofsuch T cell-based therapies could be enhanced by shRNA-mediatedsilencing of genes that inhibit T cell function in the tumormicroenvironment.

Other Embodiments

It is to be understood that while the invention has been described inconjunction with the detailed description thereof, the foregoingdescription is intended to illustrate and not limit the scope of theinvention, which is defined by the scope of the appended claims. Otheraspects, advantages, and modifications are within the scope of thefollowing claims.

REFERENCES

-   1. Galon, J., et al. Type, density, and location of immune cells    within human colorectal tumors predict clinical outcome. Science    313, 1960-1964 (2006).-   2. Hamanishi, J., et al. Programmed cell death 1 ligand 1 and    tumor-infiltrating CD8+T lymphocytes are prognostic factors of human    ovarian cancer. Proceedings of the National Academy of Sciences of    the United States of America 104, 3360-3365 (2007).-   3. Mahmoud, S. M., et al. Tumor-Infiltrating CD8+ Lymphocytes    Predict Clinical Outcome in Breast Cancer. J Clin Oncol 29,    1949-1955 (2011).-   4. Topalian, S. L., et al. Safety, activity, and immune correlates    of anti-PD-1 antibody in cancer. The New England journal of medicine    366, 2443-2454 (2012).-   5. Brahmer, J. R., et al. Safety and activity of anti-PD-L1 antibody    in patients with advanced cancer. The New England journal of    medicine 366, 2455-2465 (2012).-   6. Hodi, F. S., et al. Improved Survival with Ipilimumab in Patients    with Metastatic Melanoma. N Engl J Med (2011).-   7. Barr, F. A., Elliott, P. R. & Gruneberg, U. Protein phosphatases    and the regulation of mitosis. J Cell Sci 124, 2323-2334 (2011).-   8. Pages, F., et al. In situ cytotoxic and memory T cells predict    outcome in patients with early-stage colorectal cancer. J Clin Oncol    27, 5944-5951 (2009).-   9. Shiao, S. L., Ganesan, A. P., Rugo, H. S. & Coussens, L. M.    Immune microenvironments in solid tumors: new targets for therapy.    Genes Dev 25, 2559-2572 (2011).-   10. Gabrilovich, D. I. & Nagaraj, S. Myeloid-derived suppressor    cells as regulators of the immune system. Nat Rev Immunol 9, 162-174    (2009).-   11. Topalian, S. L., Drake, C. G. & Pardoll, D. M. Targeting the    PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity. Current    opinion in immunology 24, 207-212(2012).-   12. Westbrook, T. F., et al. A genetic screen for candidate tumor    suppressors identifies REST. Cell 121, 837-848 (2005).-   13. Luo, B., et al. Highly parallel identification of essential    genes in cancer cells. Proceedings of the National Academy of    Sciences of the United States of America 105, 20380-20385 (2008).-   14. Zender, L., et al. An oncogenomics-based in vivo RNAi screen    identifies tumor suppressors in liver cancer. Cell 135, 852-864    (2008).-   15. Fidler, I. J. Biological behavior of malignant melanoma cells    correlated to their survival in vivo. Cancer research 35, 218-224    (1975).-   16. Hogquist, K. A., et al. T cell receptor antagonist peptides    induce positive selection. Cell 76, 17-27 (1994).-   17. Bellone, M., et al. Relevance of the tumor antigen in the    validation of three vaccination strategies for melanoma. Journal of    immunology 165, 2651-2656 (2000).-   18. Overwijk, W. W., et al. Tumor regression and autoimmunity after    reversal of a functionally tolerant state of self-reactive CD8+ T    cells. The Journal of experimental medicine 198, 569-580 (2003).-   19. Paolino, M. & Penninger, J. M. Cbl-b in T-cell activation. Semin    Immunopathol 32, 137-148 (2010).-   20. Zheng, Y., Zha, Y. & Gajewski, T. F. Molecular regulation of    T-cell anergy. EWBO Rep 9, 50-55 (2008).-   21. Doody, K. M., Bourdeau, A. & Tremblay, M. L. T-cell protein    tyrosine phosphatase is a key regulator in immune cell signaling:    lessons from the knockout mouse model and implications in human    disease. Immunological reviews 228, 325-341 (2009).-   22. Tamiya, T., Kashiwagi, I., Takahashi, R., Yasukawa, H. &    Yoshimura, A. Suppressors of cytokine signaling (SOCS) proteins and    JAK/STAT pathways: regulation of T-cell inflammation by SOCS1 and    SOCS3. Arterioscler Thromb Vasc Biol 31, 980-985 (2011).-   23. Muranski, P., et al. Tumor-specific Th17-polarized cells    eradicate large established melanoma. Blood 112, 362-373 (2008).-   24. Koller, B. H., Marrack, P., Kappler, J. W. & Smithies, O. Normal    development of mice deficient in beta 2M, MHC class I proteins, and    CD8+ T cells. Science 248, 1227-1230 (1990).-   25. Mochida, S., Maslen, S. L., Skehel, M. & Hunt, T. Greatwall    phosphorylates an inhibitor of protein phosphatase 2A that is    essential for mitosis. Science 330, 1670-1673 (2010).-   26. Chiang, C. W., et al. Protein phosphatase 2A dephosphorylation    of phosphoserine 112 plays the gatekeeper role for BAD-mediated    apoptosis. Mol Cell Biol 23, 6350-6362 (2003).-   27. Turtle, C. J., Hudecek, M., Jensen, M. C. & Riddell, S. R.    Engineered T cells for anti-cancer therapy. Current opinion in    immunology 24, 633-639 (2012).-   28. Restifo, N. P., Dudley, M. E. & Rosenberg, S. A. Adoptive    immunotherapy for cancer: harnessing the T cell response. Nature    reviews. Immunology 12, 269-281 (2012).-   29. Bollard, C. M., Rooney, C. M. & Heslop, H. E. T-cell therapy in    the treatment of post-transplant lymphoproliferative disease. Nat    Rev Clin Oncol 9, 510-519 (2012).-   30. Ashton, J. M., et al. Gene sets identified with oncogene    cooperativity analysis regulate in vivo growth and survival of    leukemia stem cells. Cell Stem Cell 11, 359-372 (2012).-   31. Wherry, E. J., et al. Molecular signature of CD8+ T cell    exhaustion during chronic viral infection. Immunity 27, 670-684    (2007).-   32. Parish, I. A., et al. The molecular signature of CD8+ T cells    undergoing deletional tolerance. Blood 113, 4575-4585 (2009).-   33. Macian, F., et al. Transcriptional mechanisms underlying    lymphocyte tolerance. Cell 109, 719-731 (2002).-   34. Zha, Y., et al. T cell anergy is reversed by active Ras and is    regulated by diacylglycerol kinase-alpha. Nat Immunol 7, 1166-1173    (2006).-   35. Lopes, A. R., et al. Bim-mediated deletion of antigen-specific    CD8 T cells in patients unable to control HBV infection. The Journal    of clinical investigation 118, 1835-1845 (2008).-   36. Kurella, S., et al. Transcriptional modulation of TCR, Notch and    Wnt signaling pathways in SEB-anergized CD4+ T cells. Genes Immun 6,    596-608 (2005).-   37. Xu, T., et al. Microarray analysis reveals differences in gene    expression of circulating CD8(+) T cells in melanoma patients and    healthy donors. Cancer research 64, 3661-3667 (2004).-   38. Gorer, P. A. Studies in antibody response of mice to tumour    inoculation. Br. J Cancer 4, 372-379 (1950).

What is claimed is:
 1. An immunoresponsive cell having tumor specificity comprising a vector, the vector comprising a sequence encoding a shRNA, wherein the shRNA comprises 15 contiguous nucleotides complementary to a nucleic acid sequence of SEQ ID NO:
 612. 2. The immunoresponsive cell of claim 1, wherein the immunoresponsive cell is selected from the group consisting of a tumor-infiltrating lymphocyte (TIL), a Natural Killer T cell (NKT), a cytotoxic T lymphocyte (CTL), and a CD4T cell.
 3. The immunoresponsive cell of claim 1, wherein the immunoresponsive cell expresses a tumor-specific T-cell receptor.
 4. The immunoresponsive cell of claim 1, wherein the immunoresponsive cell further comprises a vector encoding a chimeric antigen receptor (CAR), wherein the CAR comprises an antigen binding domain, a transmembrane domain, and a stimulatory domain.
 5. The immunoresponsive cell of claim 1, wherein the shRNA sequence reduces expression of Cblb.
 6. The immunoresponsive cell of claim 4, wherein the CAR is directed to a tumor antigen comprising prostate-specific membrane antigen (PSMA).
 7. The immunoresponsive cell of claim 4, wherein the CAR further comprises a costimulatory domain.
 8. A composition comprising the immunoresponsive cell of claim 1 and a pharmaceutically acceptable carrier.
 9. The composition of claim 8, further comprising an inhibitor of Cblb.
 10. The immunoresponsive cell of claim 1, wherein the sequence encoding the shRNA comprises a first sequence comprising 15-25 nucleotides complementary to SEQ ID NO: 612 and a second sequence that is the reverse complement of the first sequence with one or no mismatches, and a third sequence of 5-9 nucleotides positioned between the first and second sequences.
 11. The immunoresponsive cell of claim 10, wherein the first sequence comprises 19-25 nucleotides complementary to SEQ ID NO:
 612. 12. A method of treating cancer associated with a regulatory subunit of Cblb in a subject, the method comprising administering to the subject an autologous T cell modified to express a tumor specific T-cell receptor or chimeric antigen receptor (CAR) and an shRNA, wherein the shRNA comprises 15 contiguous nucleotides complementary a nucleic acid sequence of SEQ ID NO: 612; and wherein the CAR comprises an antigen binding domain, a transmembrane domain, a stimulatory domain, and a co-stimulatory domain.
 13. The method of claim 12, wherein the autologous T cell is selected from the group consisting of a tumor-infiltrating lymphocyte (TIL), a Natural Killer T cell (NKT), a cytotoxic T lymphocyte (CTL), and a CD4T cell.
 14. The method of claim 12, wherein the autologous T cell expresses a tumor-specific T-cell receptor.
 15. The method of claim 12, wherein the CAR is directed to a tumor antigen comprising prostate-specific membrane antigen (PSMA).
 16. A method of treating cancer associated with a regulatory subunit of Cblb in a subject in need thereof by silencing genes that inhibit T cell function comprising administering to the subject an immunoresponsive cell comprising a vector, the vector encoding a tumor-specific T-cell receptor or a chimeric antigen receptor (CAR) and a shRNA sequence, wherein the shRNA sequences comprises a sequence at least 12 contiguous nucleotides complementary to the mRNA sequence encoded by a nucleic acid sequence of SEQ ID NO:
 612. 17. The method of claim 16, wherein the CAR comprises an antigen binding domain, a transmembrane domain, a stimulatory domain, and a co-stimulatory domain.
 18. The method of claim 16, wherein the immunoresponsive cell is selected from the group consisting of a tumor-infiltrating lymphocyte (TIL), a Natural Killer T cell (NKT), a cytotoxic T lymphocyte (CTL), and a CD4T cell.
 19. The method of claim 16, wherein the immunoresponsive cell expresses a tumor-specific T-cell receptor.
 20. The method of claim 16, wherein the CAR is directed to a tumor antigen comprising prostate-specific membrane antigen (PSMA). 